Compounds Useful for Treating a Mannheimia Haemolytica or Histophilus Somni Infection

ABSTRACT

The present invention discloses compounds that are useful in the treatment of respiratory diseases of animals, especially Bovine or Swine Respiratory disease (BRD and SRD).

The present invention relates to the field of compounds for thetreatment of respiratory diseases of animals, especially of Bovine orSwine Respiratory disease (BRD or SRD).

BACKGROUND

Bovine respiratory disease (BRD) is the most common and costly diseaseaffecting beef cattle in the world. It is a complex, bacterial infectionthat causes pneumonia in calves and can possibly be fatal. The infectionis usually a sum of three codependent factors: Stress, an underlyingviral infection, and a new bacterial infection. The diagnosis of thedisease is complex since there are multiple possible causes.

The disease manifests itself most often in calves within four weeks ofweaning, when calves are sorted and often sold to different farms. Thisgives it a common nickname, “Shipping Fever.”

BRD is of major economic importance to the North American and the globalcattle industries. The United States feedlot industry estimates anannual loss as high as 1 billion dollars due to loss of production,increased labor expenses, drug costs, and death because of bovinerespiratory disease (BRD).

Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, andMycoplasma bovis are the bacterial agents that have been mostconsistently implicated in BRDViral agents include Bovine Viral Diarrhea(BVD), Infectious Bovine Rhinotracheitis (IBR), Bovine RespiratorySynctial Virus (BRSV), and Parainfluenza Type-3 Virus (PI-3).

Pasteurella is a genus of Gram-negative, facultatively anaerobicbacteria Pasteurella multocida is the cause of a range of diseases inmammals and birds, including fowl cholera in poultry, atrophic rhinitisin pigs, and bovine hemorrhagic septicemia in cattle and buffalo.

Histophilus somni is also known as Haemophilus agni, Histophilus ovisHaemophilus somnus, and Haemophilus somnifer.

Histophilus somni is a bacterium that lives in the nasal passages ofcattle. Generally speaking, H. somni infects vascular tissue (bloodvessels) and endothelium of organs, causing inflammation, thrombosis(formation of a vascular obstruction) that interrupts the blood supply,and causes local cellular death.

H. somni typically colonize in the respiratory tract, reproductivetract, and circulatory system of many herd animals such as cattle,sheep, and American bison. If H. somni infects the lungs, pneumonia canresult in rapid death. If H. somni gains access to the bloodstream, itspreads throughout the body, a condition known as septicemia.

Mannheimia haemolytica is a species of the Mannheimia genus. Mannheimiahaemolytica is a gram negative bacterium normally found in the upperrespiratory tract of healthy cattle, sheep and wild sheep. Mannheimiahaemolytica was formerly known as: Pasteurella haemolytica. M.haemolytica descends into the lungs when cattle experience stress suchas shipping, weaning, overcrowding, or viral infections and causesfibrinous and necrotizing bronchopneumonia, a chief component of thebovine respiratory disease (BRD). M. haemolytica is the bacterium mostcommonly isolated from the lungs of cattle affected with BRD in theUnited States.

Vaccinations exist for several biological BRD precursors, but themultitude of possible precursors complicates the process of choosing avaccine regime. Bacteria may be treated with common antibiotics.

Fear of antibiotic resistance caution the use of broad spectrumantibiotics and instead prefer compounds that selectively kill bacteria.

There exists a need for such compounds that treat bovine respiratorydisease (BRD) associated with Mannheimia haemolytica, Pasteurellamultocida and Histophilus somni.

Preferably these compounds are active against the bacterial causes ofBRD. Preferably the compounds are active against Mannheimia haemolytica,Pasteurella multocida and Histophilus somni. Preferably the compoundsare also active against resistant (e.g. macrolide) strains of thesebacteria.

Such strains for Mannheimia haemolytica and Pasteurella multocida aree.g. described in Rose S, et al: “Multiplex PCR to identify macrolidereseistance determinants in Mannheimia haemolytica and Pasteurellamultocida” Antimicrobial Agents and Chemotherapy, 56, 7 (2012) p.3664-3669.

Respiratory disease in swine is arguably the most important healthconcern for swine producers today. As with respiratory disease in humansand other species, respiratory disease in swine is often the result of acombination of primary and opportunistic infectious agents. In addition,adverse environmental and management conditions play an important rolein the multifactorial nature of respiratory disease in pigs.

The term swine respiratory disease (SRD) was used to describe pneumoniaof multiple etiology causing clinical disease and failure to gain weightlater in the finishing process (15 to 20 weeks of age).

Actinobacillus pleuropneumoniae is a gram-negative bacterium which isthe most common cause of pleuropneumonia in pigs. Outbreaks of A.pleuropneumoniae are usually precipitated by stress, environmentalchanges, or viral or mycoplasmal infection. The disease may presentclinically as a peracute form with sudden death; an acute form withclinical signs characterized by fever, lethargy, dyspnea, cyanosis,recumbency, and froth from the nose; or a subacute/chronic form whichdevelops after disappearance of acute signs with intermittent cough,slow growth, and exercise intolerance.

P. multocida is a gram-negative bacterium which is a cause of atrophicrhinitis and pneumonia in pigs. Bordetella bronchiseptica is agram-negative bacterium that causes rhinitis and mild to moderateturbinate atrophy and predisposes to infection with toxigenic strains ofP. multocida which causes the progressive form of atrophic rhinitis.

Mycoplasma hyopneumoniae is the primary pathogen associated withenzootic pneumonia, which occurs when M. hyopneumoniae is combined withopportunistic bacteria such as P. multocida.

Haemophilus parasuis is a gram-negative bacterium which causespolyserositis (Glässer's disease) and pneumonia in swine. Clinical signsinclude fever, anorexia, swollen joints with lameness, dyspnea, andcentral nervous system signs. Because of the incomplete efficacy ofvaccines, antibacterials are needed to treat H. parasuis infections.

Consequently there is a need for compounds for the treatment and controlof swine respiratory disease (SRD) especially when associated withPasteurella multocida, Actinobacillus pleuropneumoniae, Bordetellabronchiseptica or Haemophilus parasuis. Preferably these compounds areactive against the bacterial causes of SRD. Preferably the compounds areactive against Pasteurella multocida and Actinobacilluspleuropneumoniae. Preferably the compounds are also active againstBordetella bronchiseptica. In one embodiment they are active againstMycoplasma spp. It is therefore desirable, that such antibacterialcompounds have an effect on such bacterial pathogens involved in BRDand/or SRD but are not active against pathogens (especiallymultiresistant) that are important in human health, such asStraphylococcus spp. and Streptrococcus spp., Acinetobacter species,especially Acinetobacter baumanii.

SUMMARY OF THE INVENTION

Surprisingly it was found that at least one of the objects can be met byproviding a compound according to the formula (I):

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, whereinR¹ is selected from the group consisting of H, C(R¹¹R¹²R¹³), C(═O)R¹¹,—C(═NR¹⁴)R¹¹;R¹¹ is selected from the group consisting of H, and C₁₋₆-alkyl;R¹² is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, and C₁₋₆-alkyl substituted with a substituent        from the group consisting of —SR⁸, —OR⁹, —C(═O)OR⁹, —NR⁹R¹⁰,        —SO₂NR⁹R¹⁰, —SO₂R⁸;        R¹³ is selected from the group consisting of    -   H, C₁₋₆-alkyl, aryl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸, nitro,        —C(═O)NR⁹R¹⁰, and C₁₋₆-alkyl substituted with a substituent        selected from the group consisting of —SR⁸, —C(═O)NR⁹R¹⁰,        —SO₂R⁸, —SO₂NR⁹R¹⁰, nitro, cyano, —OR⁹, —C(═O)OR⁹,        —NR⁹C(═NR¹⁴)NR⁹R¹⁰;        or R¹³ and R² together with the N atom which R² is attached to,        form a saturated or unsaturated heterocycle having 3 to 6 ring        atoms wherein 1 ring atom is N and 0, 1 or 2 further ring atoms        are selected from N, S, and O the rest of the ring atoms being        C;        wherein when R¹³ is OH or NH₂ and R¹² is methyl then R¹¹ cannot        be H or R¹¹ cannot be methyl when R¹³ is NH₂;        R¹⁴ is selected from the group consisting of H, C₁₋₆-alkyl,        —OR⁹;        R², R³ is selected from the group consisting of    -   H, C₁₋₆-alkyl, and C₁₋₆-alkyl substituted with a substituent        from the group consisting of halogen, hydroxyl, C₁₋₆-alkoxy,        aryloxy, ester, thiol, C₁₋₆-alkyl, carbonyl, —SR⁸, —SO₂R⁸,        —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, cyano, —NR⁹R¹⁰, —C(═O)OR⁹, aryl,        heteroaryl, heterocycle, C₃₋₈-cycloalkyl;        R⁴ is selected from the group consisting of    -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        —OR⁹, C(═O)OR⁹, C(═O)R⁸, aryl, heterocyclyl, heteroaryl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, is optionally substituted with a        substituent selected from the group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR⁹R¹⁰,            carbonyl, nitro, C(═O)OR⁹, halogen, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, cyano, hydroxy, —SR⁸, —SO₂R⁸,            —SO₂NR⁹R¹⁰, C(═O)NR⁹R¹⁰;            R⁵ is selected from the group consisting of H, and            C₁₋₆-alkyl;            R⁶, R⁷ are independently selected from the group consisting            of    -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        aryl, heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷        is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and 0, 1, 2, or 3 further        ring atoms are selected from N, S, and O, the rest of the ring        atoms being C;    -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring        formed by R⁶, R⁷ together with the N atom to which they are        attached is optionally substituted with a substituent selected        from the group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, —NR⁹R¹⁰,            carbonyl, —C(═O)OR⁹, halogen atom, C₁₋₆-alkyl substituted            with halo, C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl,            C₁-C₆-alkyl substituted with aryl, cyano, hydroxyl, —SR⁸,            —SO₂R⁸, —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, C₁₋₆-alkyl substituted            with hydroxyl;            R⁸ is selected from the group consisting of H, C₁₋₆-alkyl;            R⁹, R¹⁰ are independently selected from the group consisting            of H, and C₁₋₆-alkyl;            L is selected from the group consisting of    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        —(NR^(L3))₀₋₁—(CH₂)₀₋₄—NR^(L3)—(CH₂)₀₋₄—,        —(NR^(L3))₀₋₁—(CR^(L1)R^(L2))₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—,        —(CR^(L1)R^(L2))₀₋₄—O—(CR^(L1)R^(L2))—,        —(CH₂)₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—C(═O)NH—(CH₂)₀₋₄—,        —C(═O)—(CR^(L1)R^(L2))—NR^(L3)C(═O)—, —C(═O)NR^(L3)—,        —NR^(L3)C(═O)—, —NR^(L3)—, —SO₂NR^(L3)—,        —NR^(L3)—C(═O)—NR^(L3)—;    -   wherein        -   R^(L1), R^(L2), R^(L3), are independently selected from the            group consisting of        -   H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with            aryl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl            substituted with heterocyclyl; or        -   R^(L1), R^(L3) together with the atoms to which they are            attached can form a saturated or unsaturated heterocyclic            ring having 3 to 8 ring atoms, wherein 1, 2, or 3, ring            atoms are selected from N, S, and O;            M is selected from the group consisting of    -   C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl, C₂₋₄alkenyl,        C₂₋₄alkynyl, —C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—    -   wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is        optionally substituted with a substituent selected from the        group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(M2)R^(M3),            carbonyl, —C(═O)OR^(M2), halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl            substituted with aryl, cyano, hydroxy, —SR^(M2), —SO₂R^(M4),            —OSO₂R^(M4), —SO₂NR^(M2)R^(M3), —C(═O)NR^(M2)R^(M3)—,            hydroxy-C₁₋₆-alkyl;    -   wherein R^(M1) is selected from the group consisting of H,        C₁₋₆-alkyl, halo, hydroxyl, and amino;    -   wherein R^(M2), R^(M3) are independently selected from the group        consisting of H, and C₁₋₆-alkyl;    -   wherein R^(M4) is selected from the group consisting of H,        C₁₋₆-alkyl, and amino;        G is selected from the group consisting of    -   —(C(R^(G2)R^(G3))₀₋₄—O—(C(R^(G2)R^(G3))₀₋₄—,        —(C(R^(G2)R^(G3))₀₋₄—S—(C(R^(G2)R^(G3))₀₋₄—,        —(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—, —C(═O)—,        —NR^(G1)C(═O)—,        —C(═O)NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—C(R^(G2)R^(G3))—C(═O)NR^(G1)—,        —CR^(G2)═CR^(G2)—, —CR^(G2)═CR^(G2)—CR^(G2)═CR^(G2)—, —C≡C—,        —C≡C—C≡C—, —CR^(G2)═CR^(G2)—C≡C—, —C≡C—CR^(G2)═CR^(G2),        —C(═O)—C≡C—, —C≡C—C(═O)— —SO₂—, —S(═O)—, —S(═O)C(R^(G2)R^(G3))—.        —C(R^(G2)R^(G3))S(═O)—, —C(R^(G2)R^(G3))—SO₂—,        —SO₂C(R^(G2)R^(G3))—;    -   wherein        -   R^(G1) is H or C₁₋₆-alkyl        -   each R^(G2), R^(G3) is independently selected from the group            consisting of        -   H, halogen atom, or C₁₋₆-alkyl;            Y is selected from the group consisting of    -   C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl,    -   wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is        optionally substituted with a substituent selected from the        group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(Y1)R^(Y2),            carbonyl, —C(═O)—OR^(Y1), halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl            substituted with aryl, cyano, hydroxy, —SR^(Y2), —SO₂R^(Y3),            —OSO₂R^(Y3), —SO₂NR^(Y1)R^(Y2), —C(═O)NR^(M2)R^(M3)—,            hydroxy-C₁₋₆-alkyl;    -   wherein R^(Y1), R^(Y2) are independently selected from the group        consisting of H, and C₁₋₆-alkyl;    -   wherein R^(Y3) is selected from the group consisting of H,        C₁₋₆-alkyl, and amino;        X is selected from the group consisting of    -   —C(═O)—, —C₁₋₆-alkyl-C(═O)—, —C₂₋₆-alkenyl-C(═O)—,        —C₂₋₆-alkynyl-C(═O)—, and —(C(R^(X1)R^(X2))—, —S(═O)—, —SO₂—;    -   wherein        -   each R^(X1), R^(X2) is selected from the group consisting of        -   H, halogen atom, substituted C₁₋₆-alkyl, or un-substituted            C₁₋₆-alkyl;        -   wherein the substituents on the substituted C₁₋₆-alkyl may            be selected from the group consisting of halogen, hydroxyl,            alkoxy, aryloxy, ester, thiol, C₁₋₆-alkyl, carbonyl,            —SR^(X3), —SO₂R^(X5), —C(═O)NR^(X3)R^(X4), cyano,            —NR^(X3)R^(X4), —C(═O)—OR^(X3), aryl, heteroaryl,            heterocycle, C₃₋₈-cycloalkyl;        -   wherein R^(X3), R^(X4) are independently selected from the            group consisting of H, or C₁₋₆-alkyl;        -   wherein R^(X5) is selected from the group consisting of H,            C₁₋₆-alkyl, and amine.

Suitably, in an embodiment of the invention and/or embodiments thereof,R⁶, R⁷ are independently selected from the group consisting of

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        aryl, heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷        is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O, the rest of        the ring atoms being C;        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring            formed by R⁶, R⁷ together with the N atom to which they are            attached is optionally substituted with a substituent            selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, —NR⁹R¹⁰,                carbonyl, —C(═O)—OR⁹, halogen atom, C₁₋₆-alkyl                substituted with halo, C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl,                heteroaryl, C₁-C₆-alkyl substituted with aryl, cyano,                hydroxy, —SR⁸, —SO₂R⁸, —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,                C₁₋₆-alkyl substituted with hydroxy;    -   wherein    -   R⁸ is selected from the group consisting of H, C₁₋₆-alkyl;    -   R⁹, R¹⁰ are independently selected from the group consisting of        H, and C₁₋₆-alkyl.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ are independently selected from

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with aryl,        C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl substituted        with heterocyclyl, or NR⁶R⁷ is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ are independently selected from

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,        C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with aryl,        C₁-C₆-alkyl substituted with heteroaryl, or NR⁶R⁷ is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O.

In yet another embodiment of the invention and/or embodiments thereof Lis selected from the group consisting of

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        —(NR^(L3))₀₋₁—(CH₂)₀₋₄—NR^(L3)—(CH₂)₀₋₄—,        —(NR^(L3))₀₋₁—(CR^(L1)R^(L2))₀₋₄—NR^(L3)—(CR^(L1)R^(L2)),        —(CR^(L1)R^(L2))₀₋₄—O—(CR^(L1)R^(L2))—,        —(CH₂)₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—C(═O)NH—(CH₂)₀₋₄—,        —C(═O)—(CR^(L1)R^(L2))—NR^(L3)C(═O)—, —C(═O)NR^(L3)—,        —NR^(L3)C(═O)—, —NR^(L3)—, —SO₂NR^(L3)—, NR^(L3)—C(═O)—NR^(L3)—    -   wherein        -   R^(L1), R^(L2), R^(L3), are independently selected from the            group consisting of        -   H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with            aryl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl            substituted with heterocyclyl; or    -   R^(L1), R^(L3) together with the atoms to which they are        attached can form a saturated or unsaturated heterocyclic ring        having 3 to 8 ring atoms, wherein 1, 2, or 3, ring atoms are        selected from N, S, and O.

In yet another embodiment of the invention and/or embodiments thereof Lis selected from the group consisting of

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        —NR^(L3)—,    -   wherein        -   R^(L3), is selected from the group consisting of        -   H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with            aryl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl            substituted with heterocyclyl.

Suitably L is selected from the group consisting of C₁₋₆-alkyl, orC₂₋₆-alkenyl. Preferably L is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—, more preferably L is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—,more preferably L is —CH₂—, or —CH₂CH₂—.

In another embodiment of the invention and/or embodiments thereof M isselected from the group consisting of

-   -   C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl, C₂₋₄alkenyl,        C₂₋₄alkynyl, —C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—,    -   wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is        optionally substituted with a substituent selected from the        group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(M2)R^(M3),            carbonyl, —C(═O)—OR^(M2), halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl            substituted with aryl, cyano, hydroxy, —SR^(M2), —SO₂R^(M4),            —OSO₂R^(M4), —SO₂NR^(M2)R^(M3), —C(═O)NR^(M2)R^(M3)—,            hydroxy-C₁₋₆-alkyl;    -   wherein R^(M1) is selected from the group consisting of H,        C₁₋₆-alkyl, halo, hydroxyl, and amino;    -   wherein R^(M2), R^(M3) are independently selected from the group        consisting of H, and C₁₋₆-alkyl;    -   wherein R^(M4) is selected from the group consisting of H,        C₁₋₆-alkyl, and amino.

Suitably M is selected from the group consisting of C₃₋₁₀-cycloalkyl,aryl, heterocyclyl, heteroaryl, C₂₋₄alkenyl, C₂₋₄alkynyl,—C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—. More suitably M isselected from the group consisting of aryl, heterocyclyl, heteroaryl,—C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—. More suitably M isselected from the group consisting of aryl, heteroaryl,—C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1)).

In another embodiment of the invention and/or embodiments thereof G isselected from the group consisting of

-   -   —(C(R^(G2)R^(G3))₀₋₄—O—(C(R^(G2)R^(G3))₀₋₄—,        —(C(R^(G2)R^(G3))₀₋₄—S—(C(R^(G2)R^(G3))₀₋₄—,        —(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—, —C(═O)—,        —NR^(G1)C(═O)—,        —C(═O)NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—C(R^(G2)R^(G3))—C(═O)NR^(G1)—,        —CR^(G2)═CR^(G2)—, —CR^(G2)═CR^(G2)—CR^(G2)═CR^(G2)—, —C≡C—,        —C≡C—C≡C—, —CR^(G2)═CR^(G2)—C≡C—, —C≡C—CR^(G2)═CR^(G2),        —C(═O)—C≡C—, —C≡C—C(═O)— —SO₂—, —S(═O)—, —S(═O)C(R^(G2)R^(G3))—.        —C(R^(G2)R^(G3))S(═O)—, —C(R^(G2)R^(G3))—SO₂—,        —SO₂C(R^(G2)R^(G3))—;    -   wherein        -   R^(G1) is H or C₁₋₆-alkyl    -   each R^(G2), R^(G3) is independently selected from the group        consisting of    -   H, halogen atom, or C₁₋₆-alkyl.

In suitable embodiments, G is selected from the group consisting of—(C(R^(G2)R^(G3))₀₋₄—O—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—S—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—, —C(═O)—,—NR^(G1)C(═O)—, —C(═O)NR^(G1)—,—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—C(R^(G2)R^(G3))—C(═O)NR^(G1)—,—CR^(G2)═CR^(G2)—, —C≡C—, —C≡C—C≡C—, —C≡C—C(═O)— —SO₂—, —S(═O)—,—S(═O)C(R^(G2)R^(G3))—. —C(R^(G2)R^(G3))S(═O)—, —C(R^(G2)R^(G3))—SO₂—,—SO₂C(R^(G2)R^(G3));

-   -   wherein        -   R^(G1) is H or C₁₋₆-alkyl        -   each R^(G2), R^(G3) is independently selected from the group            consisting of        -   H, halogen atom, or C₁₋₆-alkyl.

In suitable embodiments, G is selected from the group consisting of—C≡C—, —C≡C—C≡C—, —CR^(G2)═CR^(G2)—C≡C—, —C≡C—CR^(G2)═CR^(G2), whereinR^(G2) is selected from the group consisting of H, halogen atom, orC₁₋₆-alkyl.

In another suitable embodiments, G is selected from the group consistingof CR^(G2)═CR^(G2)—, —C≡C—, —C≡C—C≡C—, —C≡C—C(═O)—.

wherein

-   -   R^(G2) is selected from the group consisting of    -   H, halogen atom, or C₁₋₆-alkyl.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (II)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, Y, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof, Y isselected from the group consisting of

-   -   C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl,    -   wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is        optionally substituted with a substituent selected from the        group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(Y1)R^(Y2),            carbonyl, —C(═O)—OR^(Y1), halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl            substituted with aryl, cyano, hydroxy, —SR^(Y2), —SO₂R^(Y3),            —OSO₂R^(Y3), —SO₂NR^(Y1)R^(Y2), —C(═O)NR^(M2)R^(M3)—,            hydroxy-C₁₋₆-alkyl;    -   wherein R^(Y1), R^(Y2) are independently selected from the group        consisting of H, and C₁₋₆-alkyl;    -   wherein R^(Y3) is selected from the group consisting of H,        C₁₋₆-alkyl, and amino.

In embodiments of the invention and/or embodiments thereof, Y isselected from

-   -   aryl, or heteroaryl. Suitably Y is aryl. Suitably Y is phenyl.        Suitably Y is para-phenyl.

In some embodiments of the invention and/or embodiments thereof thecycloalkyl, aryl, heterocyclyl, or heteroaryl of Y is optionallysubstituted with a substituent selected from the group consisting of

-   -   C₁₋₆-alkyl, C₁₋₆-alkyloxy, NR^(Y1)R^(Y2), carbonyl,        —C(═O)—OR^(Y1), halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, cyano, hydroxy, —SR^(Y2),        —SO₂R^(Y3), —OSO₂R^(Y3), —SO₂NR^(Y1)R^(Y2),        —C(═O)NR^(M2)R^(M3)—, hydroxy-C₁₋₆-alkyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of Y isoptionally substituted with a substituent selected from the groupconsisting of C₁₋₆-alkyl, halo, halo-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl.Suitably, the cycloalkyl, aryl, heterocyclyl, or heteroaryl of Y is notsubstituted.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (III)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and embodiments thereof, X isselected from the group consisting of

-   -   —C(═O)—, —C₁₋₆-alkyl-C(═O)—, —C₂₋₆-alkenyl-C(═O)—,        —C₂₋₆-alkynyl-C(═O)—, and —(C(R^(X1))₂—, —S(═O)—, —SO₂—;    -   wherein        -   R^(X1), R^(X2), is selected from the group consisting of        -   H, halogen atom, substituted C₁₋₆-alkyl, or un-substituted            C₁₋₆-alkyl;        -   wherein the substituents on the substituted C₁₋₆-alkyl may            be selected from the group consisting of halogen, hydroxyl,            alkoxy, aryloxy, ester, thiol, C₁₋₆-alkyl, carbonyl,            —SR^(X3), —SO₂R^(X5), —C(═O)NR^(X3)R^(X4), cyano,            —NR^(X3)R^(X4), —C(═O)—OR^(X3), aryl, heteroaryl,            heterocycle, C₃₋₈-cycloalkyl;        -   wherein R^(X3), R^(X4) are independently selected from the            group consisting of H, or C₁₋₆-alkyl;        -   wherein R^(X5) is selected from the group consisting of H,            C₁₋₆-alkyl, and amine.

Suitably X is selected from the group consisting of —C(═O)—,—C₁₋₆-alkyl-C(═O)—, S(═O)—, —SO₂—. Suitably X is selected from —C(═O)—,and S(═O)—.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (IV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In another embodiments of the invention and/or embodiments thereof R²,R³ is independently selected from the group consisting of H, substitutedC₁₋₆-alkyl, or un-substituted C₁₋₆-alkyl. Suitably R² and R³ are H.

In embodiments of the invention and/or embodiments thereof R⁴ isselected from the group consisting of H, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, —OR⁸, C(═O)OR⁸, C(═O)R⁸, aryl,heterocyclyl, heteroaryl, C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkylsubstituted with heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl

-   -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, is optionally substituted with a        substituent selected from the group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR⁹R¹⁰,            carbonyl, nitro, C(═O)OR⁶, halogen, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, cyano, hydroxy, —SR⁸, —SO₂R⁸,            —SO₂NR⁹R¹⁰, C(═O)NR⁹R¹⁰.

Suitably in embodiments of the invention and/or embodiments thereof R⁴is selected from the group consisting of H, C₁₋₆-alkyl, —OR⁸, C(═O)OR⁸,C(═O)R⁸. More suitably R⁴ is selected from the group consisting of H,—OR⁸. Suitably R⁴ is —OR⁸, more suitably R⁸ is OH.

Suitably R¹ is selected from the group consisting of C(R¹¹R¹²R¹³),C(═O)R¹¹, —C(═NR¹⁴)R¹¹. Suitably R¹ is C(R¹¹R¹²R¹³). Suitably R¹ isC(═O)R¹¹. Suitably R¹ is —C(═NR¹⁴)R¹¹.

In another suitable embodiment of the present invention and/orembodiments thereof, R¹² is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, and C₁₋₆-alkyl substituted with a substituent        from the group consisting of —SR⁸, —OR⁹, —C(═O)OR⁹, —NR⁹R¹⁰,        —SO₂NR⁹R¹⁰, —SO₂R⁸.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹² is substitutedwith a substituent selected from the group consisting of

-   -   —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁸.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸, nitro, —C(═O)NR⁹R¹⁰,        and C₁₋₆-alkyl substituted with a substituent selected from the        group consisting of —SR⁸, —C(═O)NR⁹R¹⁰, —SO₂R⁸, —SO₂NR⁹R¹⁰,        nitro, cyano, —OR⁹, —C(═O)OR⁹, —NR⁹C(═NR¹⁴)NR⁹R¹⁰.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹³ is substitutedwith a substituent selected from the group consisting of —SR⁸,—C(═O)NR⁹R¹⁰, —SO₂R⁸, —SO₂NR⁹R¹⁰, nitro, cyano, —OR⁹, —C(═O)OR⁹,—NR⁹C(═NR¹⁴)NR⁹R¹⁰.

In some embodiments of the present invention and/or embodiments thereof,the aryl in R¹³ is phenyl or hydroxyphenyl.

Suitably in certain embodiments of the present invention and/orembodiments thereof, R¹³ and R² together with the N atom which R² isattached to, form a heterocycle selected from the group consisting ofaziridine, azirine, azetidine, dihydroazete, azete, diazetidine,pyrrolidine, pyrroline, pyrrole, pyrazolidine, imidazolidine,pyrrazoline, imidazoline, pyrrazole, imidazole, triazole, oxazole,isoxazole, isothiazole, thiazole, oxadiazole, thiadiazole, piperidine,pyridine, piperazine, pyridazine, pyrimidine, pyrazine, triazine,morpholine, oxazine, thiomorpholine, thiazine.

Suitably in certain embodiments of the present invention and/orembodiments thereof, when R¹³ is OH or NH₂ and R¹² is methyl then R¹¹cannot be H.

Suitably in certain embodiments of the present invention and/orembodiments thereof, when R¹³ is NH₂ and R¹² is methyl R¹¹ cannot bemethyl.

Suitably in certain embodiments of the present invention and/orembodiments thereof, when R¹³ is OH and R¹² is methyl then R¹¹ cannot bemethyl.

Suitably in certain embodiments of the present invention and/orembodiments thereof, when R¹³ is NH₂ and R¹² is H then R¹¹ cannot be H.

Suitably in certain embodiments of the present invention and/orembodiments thereof, when R¹³ is OH and R¹² is H then R¹¹ cannot be H.

Suitably in certain embodiments of the present invention and/orembodiments thereof, when R¹³ is CH₃ and R¹² is CH₃ then R¹¹ cannot beH.

The invention is also directed to method for treating an animal with aninfection by a bacteria comprising administering to the subject in needthereof an effective amount of a compound of the present inventionand/or embodiments thereof with a pharmaceutically acceptable carrier,wherein the bacteria is at least one of the bacteria selected from thegroup Pasteurella multocida, Mannheimia haemolytica and Histophilussomni. Suitably the subject is a mammal and in some embodiments, aruminant or swine.

In yet another aspect, the invention is directed to a compound accordingto the present invention and/or embodiments thereof with apharmaceutically acceptable carrier for use in the treatment of bovinerespiratory disease or swine respiratory disease.

The invention provides further a pharmaceutical composition comprisingan effective amount of a compound according to the invention and/orembodiments thereof with a pharmaceutically acceptable carrier thereof.

DETAILED DESCRIPTION

It was found that compounds according to formula (I) or thestereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, are useful in the treatment of an infection by abacteria causing Bovine Respiratory disease, such as Mannheimiahaemolytica Histophilus somni, and Pasteurella multocida, In particularthe compounds according to the invention and/or any embodiments thereofare useful in the treatment of an infection by Mannheimia haemolyticaand/or Histophilus somni. Optionally, the compounds according to theinvention and/or any embodiments thereof are useful in the treatment ofan infection by Pasteurella multocida. Advantageously, the compoundsaccording to the invention and/or any embodiments thereof are useful inthe treatment of an infection by Mannheimia haemolytica, Histophilussomni and Pasteurella multocida.

Increasingly there is a fear of multi-resistant bacteria. There istherefore a need for a specific antibiotic that can be used in aninfection of a specific bacterium. Advantageously the compoundsaccording to the invention and/or any embodiments thereof is effectiveagainst Mannheimia haemolytica, Histphilus somni and/or Pasteurellamultocida but not against other bacteria, such as those that areimportant in human health, such as Straphylococcus spp. andStreptrococcus spp., Acinetobacter species, especially Acinetobacterbaumanii.

The following abbreviations and definitions are used throughout thisapplication: Generally, reference to a certain element such as hydrogenor H is meant to include all isotopes of that element. For example, ifan R group is defined to include hydrogen or H, it also includesdeuterium and tritium.

The phrase “alkyl” refers to alkyl groups that do not containheteroatoms. Thus the phrase includes straight chain alkyl groups suchas methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl and the like. The phrase also includes branchedchain isomers of straight chain alkyl groups, including but not limitedto, the following that are provided by way of example: —CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂,—CH₂CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃,—CH(CH₃)CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃,—CH(CH₃)CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂,—CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others. Thus the phrase alkylgroups includes primary alkyl groups, secondary alkyl groups, andtertiary alkyl groups. Preferred alkyl groups include straight andbranched chain alkyl groups having 1 to 12 carbon atoms.

The phrase “substituted alkyl” refers to an alkyl group as defined abovein which one or more bonds to a carbon (s) or hydrogen (s) are replacedby a bond to non-hydrogen and non-carbon atoms. If not further definedthe “substituted alkyl” may be substituted by a group such as, but notlimited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom ingroups such as hydroxyl groups, alkoxy groups, aryloxy groups, and estergroups; a sulfur atom in groups such as thiol groups, alkyl and arylsulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; anitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as in trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups also include groups in which one or more bondsto a carbon (s) or hydrogen (s) atom is replaced by a higher-order bond(e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo,carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines,oximes, hydrazones, and nitriles. Substituted alkyl groups furtherinclude alkyl groups in which one or more bonds to a carbon (s) orhydrogen (s) atoms is replaced by a bond to an aryl, heterocyclyl group,or cycloalkyl group. Exemplary substituted alkyl groups include, amongothers, alkyl groups in which one or more bonds to a carbon or hydrogenatom is/are replaced by one or more bonds to fluorine atoms.

Another exemplary substituted alkyl group is the trifluoromethyl groupand other alkyl groups that contain the trifluoromethyl group. Otherexemplary substituted alkyl groups include those in which one or morebonds to a carbon or hydrogen atom is replaced by a bond to an oxygenatom such that the substituted alkyl group contains a hydroxyl, alkoxy,or aryloxy group. Still other exemplary substituted alkyl groups includealkyl groups that have an amine, or a substituted or unsubstitutedalkylamine, dialkylamine, arylamine, (alkyl) (aryl) amine, diarylamine,heterocyclylamine, diheterocyclylamine, (alkyl) (heterocyclyl) amine, or(aryl) (heterocyclyl) amine group.

The phrase “alkenyl” refers to straight and branched chain and cyclicgroups such as those described with respect to alkyl groups as definedabove, except that at least one double bond exists between two carbonatoms. Examples include, but are not limited to vinyl, —CH═C(H)(CH₃),—CH═C(CH₃)₂, —C(CH₃)═C(H)₂, —C(CH)═C(H)(CH₃), —C(CH₂CH₃)═CH₂,cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl,and hexadienyl among others.

The phrase “substituted alkenyl” has the same meaning with respect toalkenyl groups that substituted alkyl groups had with respect tounsubstituted alkyl groups. A substituted alkenyl group includes alkenylgroups in which a non-carbon or non-hydrogen atom is bonded to a carbondouble bonded to another carbon and those in which one of the non-carbonor non-hydrogen atoms is bonded to a carbon not involved in a doublebond to another carbon.

The phrase “alkynyl” refers to straight and branched chain groups suchas those described with respect to alkyl groups as defined above, exceptthat at least one triple bond exists between two carbon atoms. Examplesinclude, but are not limited to —C≡C(H), —C≡C(CH₃), —C≡C(CH₂CH₃),—C(H₂)C≡C(H), —C(H)₂C≡C(CH₃), and —C(H)₂C≡C(CH₂CH₃) among others.

The phrase “substituted alkynyl” has the same meaning with respect toalkynyl groups that substituted alkyl groups had with respect tounsubstituted alkyl groups. A substituted alkynyl group includes alkynylgroups in which a non-carbon or non-hydrogen atom is bonded to a carbontriple bonded to another carbon and those in which a non-carbon ornon-hydrogen atom is bonded to a carbon not involved in a triple bond toanother carbon.

The phrase “cycloalkyl” refers to a non-aromatic monocyclic orpolycyclic alkyl group consisting solely of carbon and hydrogen atoms,and which may be saturated or unsaturated. Cycloalkyl may include fusedor bridged ring systems, having from three to fifteen carbon atoms,preferably having from three to ten carbon atoms (C₃-C₁₀-cycloalkyl),and which may be saturated or unsaturated. Monocyclic radicals include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptly, cyclooctyl, and the like. Polycyclic radicals include, forexample, adamantine, norbornane, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. If not furtherdefined, cycloalkyl may be substituted with substituents as indicatedabove with substituted alkyl group.

The phrase “heterocyclic ring” refers to both aromatic, “heteroaryl” andnonaromatic, “heterocyclyl”, ring compounds including monocyclic,bicyclic, and polycyclic ring compounds such as, but not limited to,quinuclidinyl, containing 3 or more ring members of which one or more isa heteroatom such as, but not limited to, N, O, and S.

Heterocyclyl refers to a 3- to 18-membered non-aromatic ring radicalwhich consists of two to seventeen carbon atoms and from one to tenheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic or polycyclic ringsystem, which may include fused or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heterocyclyl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized;and the heterocyclyl radical may be partially or fully saturated.Although the phrase “unsubstituted heterocyclyl” includes condensedheterocyclic rings such as benzimidazolyl, it does not includeheterocyclyl groups that have other groups such as alkyl or halo groupsbonded to one of the ring members as compounds such as2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples ofheterocyclyl groups include, but are not limited to: unsaturated 3 to 8membered rings containing 1 to 4 nitrogen atoms such as, but not limitedto pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl,lu-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g.1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered ringscontaining 1 to 4 nitrogen atoms such as, but not limited to,pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensedunsaturated heterocyclic groups containing 1 to 4 nitrogen atoms suchas, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl;unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl,oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to,morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl,benzoxadiazolyl, benzoxazinyl (e.g. 2H-1,4-benzoxazinyl etc.);unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1to 3 nitrogen atoms such as, but not limited to, thiazolyl,isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.); saturated 3 to 8 memberedrings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as,but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8membered rings containing 1 to 2 sulfur atoms such as, but not limitedto, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene,tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limitedto, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g.2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered ringscontaining oxygen atoms such as, but not limited to furyl; unsaturatedcondensed heterocyclic rings containing 1 to 2 oxygen atoms such asbenzodioxolyl (e.g. 1,3-benzodioxoyl, etc.); unsaturated 3 to 8 memberedrings containing an oxygen atom and 1 to 2 sulfur atoms such as, but notlimited to, dihydrooxathiinyl; saturated 3 to 8 membered ringscontaining 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfuratoms such as benzothienyl, benzodithiinyl; and unsaturated condensedheterocyclic rings containing an oxygen atom and 1 to 2 oxygen atomssuch as benzoxathiinyl. Heterocyclyl group also include those describedabove in which one or more S atoms in the ring is double-bonded to oneor two oxygen atoms (sulfoxides and sulfones). For example, heterocyclylgroups include tetrahydrothiophene, tetrahydrothiophene oxide, andtetrahydrothiophene 1,1-dioxide. Exemplary heterocyclyl groups contain 5or 6 ring members. Other exemplary heterocyclyl groups includemorpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, thiomorpholine,thiomorpholine in which the S atom of the thiomorpholine is bonded toone or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one,pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan, andtetrahydrofuran. The phrase “substituted heterocyclyl” refers to aheterocyclyl group as defined above in which one of the ring members isbonded to a non-hydrogen atom such as described above with respect tosubstituted alkyl groups and substituted aryl groups. Examples, include,but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl,5-chlorobenzthiazolyl, 1-methyl piperazinyl, and 2-chloropyridyl amongothers.

The phrase “aryl” refers to aryl groups that do not contain heteroatoms.Thus the phrase includes, but is not limited to, groups such as phenyl,biphenyl, anthracenyl, naphtenyl by way of example. Although the phrase“unsubstituted aryl” includes groups containing condensed rings such asnaphthalene, it does not include aryl groups that have other groups suchas alkyl or halo groups bonded to one of the ring members, as arylgroups such as tolyl are considered herein to be substituted aryl groupsas described below. An exemplary unsubstituted aryl group is phenyl.Unsubstituted aryl groups may be bonded to one or more carbon atom(s),oxygen atom(s), nitrogen atom(s), and/or sulfur atom (s) in the parentcompound, however.

The phrase “substituted aryl group” has the same meaning with respect tounsubstituted aryl groups that substituted alkyl groups had with respectto unsubstituted alkyl groups. However, a substituted aryl group alsoincludes aryl groups in which one of the aromatic carbons is bonded toone of the non-carbon or non-hydrogen atoms described above and alsoincludes aryl groups in which one or more aromatic carbons of the arylgroup is bonded to a substituted and/or unsubstituted alkyl, alkenyl, oralkynyl group as defined herein. This includes bonding arrangements inwhich two carbon atoms of an aryl group are bonded to two atoms of analkyl, alkenyl, or alkynyl group to define a fused ring system (e.g.dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase “substitutedaryl” includes, but is not limited to tolyl, and hydroxyphenyl amongothers. If not further defined the “substituted aryl group” may besubstituted by a group such as straight and branched chain alkyl groups,—CH₃, —C₂H₅, —CH₂OH, —OH, —OCH₃, —OC₂H₅, —OCF₃, —CN, —NO₂, —CO₂H,—CO₂CH₃, —CONH₂, —NH₂, —F, —Cl, Br, —CF₃, —N(CH₃)₂, —NHSO₂CH₃, —NHCOCH₃.

The term “heteroaryl”, as used herein, refers to a cyclic or bicyclicaromatic radical having from five to ten ring atoms in each ring ofwhich one atom of the cyclic or bicyclic ring is selected from S, O andN; zero, one or two ring atoms are additional heteroatoms independentlyselected from S, O and N; and the remaining ring atoms are carbon, theradical being joined to the rest of the molecule via any of the ringatoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, andnaphthyridinyl, and the like.

The term “substituted heteroaryl” as used herein refers to a heteroarylgroup as defined herein substituted by independent replacement of one,two or three of the hydrogen atoms thereon. Exemplary substituents mayinclude Cl, Br, F, I, OH, CN, C₁₋₃-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxysubstituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino,dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyland carboxamide. In addition, any one substituent may be an aryl,heteroaryl, or heterocycloalkyl group.

Exemplary substituents include straight and branched chain alkyl groups,—CH₃, —C₂H₅, —CH₂OH, —OH, —OCH₃, —OC₂H₅, —OCF₃, —CN, —NO₂, —CO₂H,—CO₂CH₃, —CONH₂, —NH₂, —F, —Cl, —Br, —CF₃, —N(CH₃)₂, —NHSO₂CH₃,—NHCOCH₃.

The term “biaryl” refers to a group or substituent to which two arylgroups, which are not condensed to each other, are bound. Exemplarybiaryl compounds include, for example, phenylbenzene, diphenyldiazene,4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl) benzene,diphenyl ketone, (4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine,(phenylmethoxy)benzene, and the like. Preferred optionally substitutedbiaryl groups include: 2-(phenylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 1,4-diphenylbenzene, N-[4-(2-phenylethynyl)phenyl]-2-[benzylamino]acetamide, 2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide, 2-amino-N-[4-(2-phenylethynyl) phenyl]acetamide,2-(cyclopropylamino)-N-[4-(2-phenylethynyl) phenyl]acetamide,2-(ethylamino)-N-[4-(2-phenylethynyl) phenyl]acetamide,2-[(2-methylpropyl) amino]-N-[4-(2-phenylethynyl) phenyl]acetamide,5-phenyl-2H-benzo [d]1,3-dioxolene, 2-chloro-I-methoxy4-phenylbenzene,2-[(imidazolylmethyl) amino]-N-[4-(2-phenylethynyl) phenyl]acetamide,4-phenyl-1-phenoxybenzene, N-(2-aminoethyl) [4-(2-phenylethynyl)phenyl]carboxamide, 2-{[(4-fluorophenyl)methyl]amino}-N-[4-(2-phenylethynyl) phenyl]acetamide,2-{[(4-methylphenyl) methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide, 4-phenyl-1-(trifluoromethyl) benzene,1-butyl-4-phenylbenzene, 2-(cyclohexylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-(ethylmethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-(butylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, N-[4-(2-phenylethynyl) phenyl]-2-(4-pyridylamino)acetamide, N-[4-(2-phenylethynyl) phenyl]-2-(quinuclidin-3-ylamino)acetamide, N-[4-(2-phenylethynyl) phenyl]pyrrolidin-2-ylcarboxamide,2-amino-3-methyl-N-[4-(2-phenylethynyl) phenyl]butanamide,4-(4-phenylbuta-1,3-diynyl) phenylamine,2-(dimethylamino)-N-[4-(4-phenylbuta-1,3-diynyl) phenyl]acetamide,2-(ethylamino)-N-[4-(4-phenylbuta-1, 3-diynyl) phenyl]acetamide,4-ethyl-1-phenylbenzene, 1-[4-(2-phenylethynyl) phenyl]ethan-1-one,N-(1-carbamoyl-2-hydroxypropyl) [4-(4-phenylbuta-1,3-diynyl)phenyl]carboxamide, N-[4-(2-phenylethynyl) phenyl]propanamide,4-methoxyphenyl phenyl ketone, phenyl-N-benzamide,(tert-butoxy)-N-[(4-phenylphenyl) methyl]carboxamide,2-(3-phenylphenoxy) ethanehydroxamic acid, 3-phenylphenyl propanoate,1-(4-ethoxyphenyl)-4-methoxybenzene, and [4-(2-phenylethynyl)phenyl]pyrrole.

The term “heteroarylaryl” refers to a biaryl group where one of the arylgroups is a heteroaryl group. Exemplary heteroarylaryl groups include,for example, 2-phenylpyridine, phenylpyrrole, 3-(2-phenylethynyl)pyridine, phenylpyrazole,5-(2-phenylethynyl)-1,3-dihydropyrimidine-2,4-dione,4-phenyl-1,2,3-thiadiazole, 2-(2-phenylethynyl) pyrazine,2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)furan,3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Optionallysubstituted heteroarylaryl groups include: 5-(2-phenylethynyl)pyrimidine-2-ylamine, 1-methoxy-4-(2-thienyl) benzene,1-methoxy-3-(2-thienyl) benzene, 5-methyl-2-phenylpyridine,5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl) phenyl]furan,3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene, (hydroxyimino)(5-phenyl (2-thienyl)) methane, 5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene, 2-(4-ethylphenyl) thiophene,4-methylthio-1-(2-thienyl) benzene, 2-(3-nitrophenyl) thiophene,(tert-butoxy)-N-[(5-phenyl (3-pyridyl)) methyl]carboxamide,hydroxy-N-[(5-phenyl (3-pyridyl)) methyl]amide, 2-(phenyhnethylthio)pyridine, and benzylimidazole.

The term “heteroaryl” refers to a biaryl group where both of the arylgroups is a heteroaryl group. Exemplary heteroarylgroups include, forexample, 3-pyridylimidazole, 2-imidazolylpyrazine, and the like.Preferred optionally substituted heteroaryl groups include:2-(4-piperazinyl-3-pyridyl) furan, diethyl (3-pyrazin-2-yl (4-pyridyl))amine, and dimethyl {2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl)}amine.

“Optionally substituted” refers to the optional replacement of hydrogenwith one or more monovalent or divalent radicals. Optionally substitutedgroups include those described herein, for each group in which adistinct definition for substitution is supplied. Additionally, suitablesubstitution groups include, for example, hydroxyl, nitro, amino, imino,cyano, halo, thio, thioamido, amidino, imidino, oxo, oxamidino,methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl,substituted alkyl, haloloweralkyl, loweralkoxy, haloloweralkoxy,loweralkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,cyanoalkyl, benzyl, pyridyl, pyrazolyl, pyrrole, thiophene, imidazolyl,and the like.

The term “protected” with respect to hydroxyl groups, amine groups, andsulfhydryl groups refers to forms of these functionalities that areprotected from undesirable reaction with a protecting group known tothose skilled in the art such as those set forth in Protective Groups inOrganic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, NewYork, N.Y., (3rd Edition, 1999) that can be added or removed using theprocedures set forth therein. Examples of protected hydroxyl groupsinclude, but are not limited to, silyl ethers such as those obtained byreaction of a hydroxyl group with a reagent such as, but not limited to,t-butyldimethyl-chlorosilane, trimethylchlorosilane,triisopropylchlorosilane, triethylchlorosilane; substituted methyl andethyl ethers such as, but not limited to methoxymethyl ether,methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether,2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethylether, allyl ether, benzyl ether; esters such as, but not limited to,benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.

Examples of protected amine groups include, but are not limited to,amides such as, formamide, acetamide, trifluoroacetamide, and benzamide;imides, such as phthalimide, and dithiosuccinimide; and others. Examplesof protected sulfhydryl groups include, but are not limited to,thioether such as S-benzyl thioether, and S-4-picolyl thioether;substituted S-methyl derivatives such as hemithio, dithio and aminothioacetals; and others.

A “pharmaceutically acceptable salt” includes a salt with an inorganicbase, organic base, inorganic acid, organic acid, or basic or acidicamino acid. As salts of inorganic bases, the invention includes, forexample, alkali metals such as sodium or potassium; alkaline earthmetals such as calcium and magnesium or aluminum; and ammonia. As saltsof organic bases, the invention includes, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine, andtriethanolamine. As salts of inorganic acids, the instant inventionincludes, for example, hydrochloric acid, hydroboric acid, nitric acid,sulfuric acid, and phosphoric acid. As salts of organic acids, theinstant invention includes, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basicamino acids, the instant invention includes, for example, arginine,lysine and ornithine. Acidic amino acids include, for example, asparticacid and glutamic acid.

As used herein, the term “pharmaceutically acceptable ester” refers toesters that hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.

Representative examples of particular esters include, but are notlimited to, formates, acetates, propionates, butyrates, acrylates andethylsuccinates.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formula, for example byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S.Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention.

The term “antibacterial agent” refers to agents synthesized or modifiedin the laboratory that have either bactericidal or bacteriostaticactivity.

An “active” agent in this context will inhibit the growth of Mannheimiahaemolytica, Histophilus somni, and/or Pasteurella multocidaa.

The term “inhibiting the growth” indicates that the rate of increase inthe numbers of a population of a particular bacterium is reduced. Thus,the term includes situations in which the bacterial population increasesbut at a reduced rate, as well as situations where the growth of thepopulation is stopped, as well as situations where the numbers of thebacteria in the population are reduced or the population eveneliminated. If an enzyme activity assay is used to screen forinhibitors, one can make modifications in uptake/efflux, solubility,half-life, etc. to compounds in order to correlate enzyme inhibitionwith growth inhibition. The activity of antibacterial agents is notnecessarily limited to bacteria but may also encompass activity againstparasites, virus, and fungi.

The present invention provides compounds that are useful in thetreatment of an infection by Mannheimia haemolytica, and/or Histophilussomni and/or Pasteurella multocida, pharmaceutical formulationsincluding the compounds and methods of treating an infection caused byMannheimia haemolytica and/or Histophilus somni.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹ is selected from the group consisting ofC(R¹¹R¹²R¹³), C(═O)R¹¹, —C(═NR¹⁴)R¹¹. Suitably R¹ is C(R¹¹R¹²R¹³).Suitably R¹ is C(═O)R¹¹. Suitably R¹ is —C(═NR¹⁴)R¹¹.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (V)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹,R¹², R¹³ are defined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (VI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁵, R⁶, R⁷, and R¹¹,are defined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (VII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁵, R⁶, R⁷, and R¹¹,R¹⁴ are defined as in any of the embodiments described herein.

Suitably R¹¹ is selected from the group consisting of H, and C₁₋₆-alkyl,more suitably C₁₋₆-alkyl.

In another suitable embodiment of the present invention and/orembodiments thereof, R¹² is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, and C₁₋₆-alkyl substituted with a substituent        from the group consisting of —SR⁸, —OR⁹, —C(═O)OR⁹, —NR⁹R¹⁰,        —SO₂NR⁹R¹⁰, —SO₂R⁸.

In another suitable embodiment of the present invention and/orembodiments thereof, R¹² is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, and C₁₋₆-alkyl substituted with a substituent        from the group consisting of —SR⁸, —OR⁹, —C(═O)OR⁹, —NR⁹R¹⁰,        —SO₂NR⁹R¹⁰, —SO₂R⁸.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹² is substitutedwith a substituent selected from the group consisting of

-   -   —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁸.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹² is substitutedwith a substituent selected from the group consisting of

-   -   —SCH3, —OH, —NH₂, —SO₂CH₃.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, aryl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸, nitro,        —C(═O)NR⁹R¹⁰, and C₁₋₆-alkyl substituted with a substituent        selected from the group consisting of —SR⁸, —C(═O)NR⁹R¹⁰,        —SO₂NR⁹R¹⁰, —SO₂R⁸, nitro, cyano, —OR⁹, —C(═O)OR⁹,        —NR⁹C(═NR¹⁴)NR⁹R¹⁰.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, aryl, —SR⁸, —SO₂R⁸, nitro, —C(═O)NR⁹R¹⁰, and        C₁₋₆-alkyl substituted with a substituent selected from the        group consisting of —SR⁸, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁸,        nitro, cyano, —OR⁹, —C(═O)OR⁹, —NR⁹C(═NR¹⁴)NR⁹R¹⁰.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸, nitro, —C(═O)NR⁹R¹⁰,        and C₁₋₆-alkyl substituted with a substituent selected from the        group consisting of —SR⁸, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁸,        nitro, cyano, —OR⁹, —C(═O)OR⁹, —NR⁹C(═NR¹⁴)NR⁹R¹⁰.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, —SR⁸, —SO₂R⁸, nitro, —C(═O)NR⁹R¹⁰, and C₁₋₆-alkyl        substituted with a substituent selected from the group        consisting of —SR⁸, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁸, nitro,        cyano, —OR⁹, —C(═O)OR⁹, —NR⁹C(═NR¹⁴)NR⁹R¹⁰.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸, and C₁₋₆-alkyl        substituted with a substituent selected from the group        consisting of —SR⁸, —C(═O)NR⁹R¹⁰, —SO₂R⁸, —SO₂NR⁹R¹⁰, nitro,        cyano, —OR⁹, —C(═O)OR⁹, —NR⁹C(═NR¹⁴)NR⁹R¹⁰.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, —SR⁸, —SO₂R⁸, and C₁₋₆-alkyl substituted with a        substituent selected from the group consisting of —SR⁸,        —C(═O)NR⁹R¹⁰, —SO₂R⁸, —SO₂NR⁹R¹⁰, nitro, cyano, —OR⁹, —C(═O)OR⁹,        —NR⁹C(═NR¹⁴)NR⁹R¹⁰.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   H, C₁₋₆-alkyl, —SR³, —SO₂R⁸.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   C₁₋₆-alkyl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   C₁₋₆-alkyl, —SR³, —SO₂R⁸.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   —SR⁸, —OR⁹, —SO₂R.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   —SR⁸, and —SO₂R⁸.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is selected from the group consisting of

-   -   —SR⁸, and —SO₂R⁸

and wherein R¹¹ and R¹² are methyl.

In some embodiments of the present invention and/or embodiments thereof,R¹³ is not OH or NH₂.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹³ is substitutedwith a substituent selected from the group consisting of —SR⁸,—C(═O)NR⁹R¹⁰, —SO₂R⁸, —SO₂NR⁹R¹⁰, nitro, cyano, —OR⁹, —C(═O)OR⁹,—NR⁹C(═NR¹⁴)NR⁹R¹⁰.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹³ is substitutedwith a substituent selected from the group consisting of —SR⁸,—C(═O)NR⁹R¹⁰, —SO₂R⁸, —SO₂NR⁹R¹⁰, nitro, —OR⁹, —C(═O)OR⁹.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹³ is substitutedwith a substituent selected from the group consisting of —SR⁸,—SO₂NR⁹R¹⁰, SO₂R⁸, —OR⁹.

Suitably in certain embodiments of the present invention and/orembodiments thereof, the substituted C₁₋₆-alkyl in R¹³ is substitutedwith a substituent selected from the group consisting of —SCH₃, —SO₂CH₃,—OH.

In some embodiments of the present invention and/or embodiments thereof,R¹³ and R² together with the N atom which R² is attached to, form asaturated or unsaturated heterocycle having 3 to 6 ring atoms wherein 1ring atom is N and 0, 1 or 2 further ring atoms are selected from N, S,and O the rest of the ring atoms being C.

Suitably in certain embodiments of the present invention and/orembodiments thereof, R¹³ and R² together with the N atom which R² isattached to, form a heterocycle selected from the group consisting ofaziridine, azirine, azetidine, dihydroazete, azete, diazetidine,pyrrolidine, pyrroline, pyrrole, pyrazolidine, imidazolidine,pyrrazoline, imidazoline, pyrrazole, imidazole, triazole, oxazole,isoxazole, isothiazole, thiazole, oxadiazole, thiadiazole, piperidine,pyridine, piperazine, pyridazine, pyrimidine, pyrazine, triazine,morpholine, oxazine, thiomorpholine, thiazine.

Suitably in certain embodiments of the present invention and/orembodiments thereof, R¹³ and R² together with the N atom which R² isattached to, form a heterocycle selected from the group consisting ofpyrrolidine, pyrroline, pyrrole, pyrazolidine, imidazolidine,pyrrazoline, imidazoline, pyrrazole, imidazole, triazole, oxazole,isoxazole, isothiazole, thiazole, oxadiazole, thiadiazole, piperidine,pyridine, piperazine, pyridazine, pyrimidine, pyrazine, triazine,morpholine, oxazine, thiomorpholine, thiazine.

Suitably in certain embodiments of the present invention and/orembodiments thereof, R¹³ and R² together with the N atom which R² isattached to, form a heterocycle selected from the group consisting ofpyrrolidine, pyrroline, pyrrole, pyrazolidine, imidazolidine,pyrrazoline, imidazoline, pyrrazole, imidazole, triazole, oxazole,isothiazole, thiazole, piperidine, pyridine, piperazine, pyrimidine,pyrazine, morpholine, thiomorpholine.

Suitably in certain embodiments of the present invention and/orembodiments thereof, R¹³ and R² together with the N atom which R² isattached to, form a heterocycle selected from the group consisting ofpyrrolidine, pyrroline, pyrrole, imidazole, oxazole, thiazole,piperidine, pyridine, piperazine, pyrimidine, morpholine.

Suitably in certain embodiments of the present invention and/orembodiments thereof, R¹³ and R² together with the N atom which R² isattached to, form a heterocycle selected from the group consisting ofpyrrolidine, imidazoline, oxazole, thiazole, piperidine, pyridine,morpholine. Suitably in certain embodiments of the present inventionand/or embodiments thereof, R¹³ and R² together with the N atom which R²is attached to, form a heterocycle selected from the group consisting ofpyrrolidine, pyrroline, pyrrole, imidazole, oxazole, isoxazole,isothiazole, thiazole, thiadiazole, piperidine, pyridine, piperazine,pyrimidine, pyrazine, morpholine, thiomorpholine.

Suitably when R¹³ is OH or NH₂ and R¹² is methyl then R¹¹ cannot be H.

Suitably when R¹³ is NH₂ and R¹² is methyl R¹¹ cannot be methyl.

Suitably when R¹³ is OH and R¹² is methyl then R¹¹ cannot be methyl.

Suitably when R¹³ is NH₂ and R¹² is H then R¹¹ cannot be H.

Suitably when R¹³ is OH and R¹² is H then R¹¹ cannot be H.

Suitably when R¹³ is CH₃ and R¹² is CH₃ then R¹¹ cannot be H.

Suitably in certain embodiments of the present invention and/orembodiments thereof, R¹⁴ is selected from the group consisting of H,C₁₋₆-alkyl, —OR⁹. Suitably in certain embodiments of the presentinvention and/or embodiments thereof, R¹⁴ is selected from the groupconsisting of H, C₁₋₆-alkyl, —OH.

Optionally, in an embodiment of the invention and/or embodiments thereofR⁶, R⁷ are independently selected from the group consisting of

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        aryl, heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷        is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O;    -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring        formed by R⁶, R⁷ together with the N atom to which they are        attached is optionally substituted with a substituent selected        from the group consisting of    -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, —NR⁹R¹⁰, carbonyl,        —C(═O)—OR⁹, halogen atom, C₁₋₆-alkyl substituted with halo,        C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl        substituted with aryl, cyano, hydroxy, —SR⁸, —SO₂R⁸, —SO₂NR⁹R¹⁰,        —C(═O)NR⁹R¹⁰, C₁₋₆-alkyl substituted with hydroxy;    -   wherein    -   R⁸ is selected from the group consisting of H, and C₁₋₆-alkyl;    -   R⁹, R¹⁰ are independently selected from the group consisting of        H, and C₁₋₆-alkyl.

Optionally, in an embodiment of the invention and/or embodimentsthereof, R⁶, R⁷ are independently selected from the group consisting of

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        aryl, heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷        is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O;    -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring        formed by R⁶, R⁷ together with the N atom to which they are        attached is optionally substituted with a substituent selected        from the group consisting of    -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, —NR⁹R¹⁰, carbonyl, halogen,        C₁₋₆-alkyl substituted with halo, aryl, heteroaryl, C₁-C₆-alkyl        substituted with aryl, cyano, hydroxy, —SR⁸, —SO₂R³, —SO₂NR⁹R¹⁰,        —C(═O)NR⁹R¹⁰, C₁₋₆-alkyl substituted with hydroxy;    -   wherein    -   R⁸ is selected from the group consisting of H, C₁₋₆-alkyl;    -   R⁹, R¹⁰ are independently selected from the group consisting of        H, and C₁₋₆-alkyl.

Optionally, in an embodiment of the invention and/or embodimentsthereof, R⁶, R⁷ are independently selected from the group consisting of

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        aryl, heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷        is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O;    -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring        formed by R⁶, R⁷ together with the N atom to which they are        attached is optionally substituted with a substituent selected        from the group consisting of    -   C₁₋₆-alkyl, —NR⁹R¹⁰, carbonyl, halogen, cyano, hydroxy, —SR⁸,        —SO₂R⁸, —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰;    -   wherein    -   R⁸ is selected from the group consisting of H, C₁₋₆-alkyl;    -   R⁹, R¹⁰ are independently selected from the group consisting of        H, and C₁₋₆-alkyl.

Optionally, in an embodiment of the invention and/or embodimentsthereof, R⁶, R⁷ are independently selected from the group consisting of

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        aryl, heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷        is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O;    -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring        formed by R⁶, R⁷ together with the N atom to which they are        attached is optionally substituted with a substituent selected        from the group consisting of    -   C₁₋₆-alkyl, carbonyl, halogen, amino, cyano, hydroxyl.

Optionally, in an embodiment of the invention and/or embodimentsthereof, R⁶, R⁷ are independently selected from H, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted withheteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷ is NO₂or

-   -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O;

Suitably, in an embodiment of the invention and/or embodiments thereof,R⁶, R⁷ are independently selected from the group consisting of

-   -   H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        aryl, heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted with        heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷        is NO₂ or    -   R⁶, R⁷ together with the N atom to which they are attached can        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S, and O;        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring            formed by R⁶, R⁷ together with the N atom to which they are            attached is optionally substituted with a substituent            selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, —NR⁹R¹⁰,                carbonyl, —C(═O)—OR⁹, halogen atom, C₁₋₆-alkyl                substituted with halo, C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl,                heteroaryl, C₁-C₆-alkyl substituted with aryl, cyano,                hydroxy, —SR⁸, —SO₂R⁸, —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,                C₁₋₆-alkyl substituted with hydroxy;        -   wherein    -   R⁸ is selected from the group consisting of H, C₁₋₆-alkyl;    -   R⁹, R¹⁰ are independently selected from the group consisting of        H, and C₁₋₆-alkyl.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ together with the N atom to which they are attached can form asaturated or unsaturated heterocyclic ring having 3 to 10 ring atoms,wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further ring atomsare selected from N, S, and O.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ together with the N atom to which they are attached can form asaturated or unsaturated heterocyclic ring having 3 to 8 ring atoms,wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further ring atomsare selected from N, S, and O.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ together with the N atom to which they are attached can form asaturated or unsaturated heterocyclic ring selected from the groupconsisting of azetidinyl, azetyl, diazetidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl,imidazolinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, isothiazolyl, thiazolyl, oxoadiazolyl, thiadiazolyl,oxazolidonyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, oxazinyl,thiomorpholinyl, thiazinyl, thiomorpholinyl dioxide, indolyl, indolinyl,isoindolyl, benzimidazolyl, azaindolyl, azepanyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, decahydroisoquinolinyl,decahydroquinolinyl, quinolonyl, isoquinolinyl.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ together with the N atom to which they are attached can form asaturated or unsaturated heterocyclic ring selected from the groupconsisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl,imidazolidinyl, pyrazolinyl, imidazolinyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl,thiadiazolyl, oxazolidonyl, piperidinyl, pyridinyl, piperazinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl,thiomorpholinyl, thiazinyl, thiomorpholinyl dioxide, indolyl, indolinyl,benzimidazolyl, azepanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,decahydroisoquinolinyl, decahydroquinolinyl, quinolonyl, isoquinolinyl.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ together with the N atom to which they are attached can form asaturated or unsaturated heterocyclic ring selected from the groupconsisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl,pyrazolinyl, imidazolinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, thiadiazolyl, piperidinyl, pyridinyl, piperazinyl,pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyldioxide, indolinyl, benzimidazolyl, azepanyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, decahydroisoquinolinyl, decahydroquinolinyl,quinolonyl, isoquinolinyl.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ together with the N atom to which they are attached can form asaturated or unsaturated heterocyclic ring selected from the groupconsisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl,pyrazolinyl, imidazolinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, thiadiazolyl, piperidinyl, pyridinyl, piperazinyl,pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyldioxide, indolinyl, benzimidazolyl, azepanyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, decahydroisoquinolinyl, decahydroquinolinyl,quinolonyl, isoquinolinyl.

In yet another embodiment of the invention and/or embodiments thereof,R⁶, R⁷ together with the N atom to which they are attached can form asaturated or unsaturated heterocyclic ring selected from the groupconsisting of morpholinyl, thiomorpholinyl dioxide, piperidinyl,piperazinyl, tetrahydroisoquinolinyl, pyrrolidinyl, azepanyl,pyrrolinyl,

Suitably, in an embodiment of the invention and/or embodiments thereof—NR⁶R⁷ is selected from the group consisting of

Suitably, in an embodiment of the invention and/or embodiments thereof—NR⁶R⁷ is selected from the group consisting of (a-1), (a-3), (a-5),(a-9), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27),(a-28), (a-29), (a-30), (a-31), (a-33), (a-34), (a-35), (a-36), (a-42),(a-43), (a-46), (a-55), (a-64), (a-65), (a-82), (a-83), (a-84), (a-98),(a-99), (a-100), (a-101), (a-102), (a-103), (a-104), (a-105), (a-106),(a-107), (a-108), (a-109), (a-110), (a-111), (a-112), (a-113), (a-114),(a-115), (a-116), (a-117), (a-118), (a-119), (a-120), (a-121), (a-122),(a-123), (a-124), (a-125), (a126), (a-127), (a-128), (a-129), (a-130),and (a-131).

Suitably, in an embodiment of the invention and/or embodiments thereof—NR⁶R⁷ is selected from the group consisting of (a-1), (a-3), (a-5),(a-9), (a-20), (a-34), (a-35), (a-36), (a-42), (a-46), (a-55), (a-64),(a-65), (a-98), (a-99), (a-100), (a-103), (a-104), (a-105), (a-106),(a-107), (a-108), (a-120), (a-121), (a-125), (a126), and (a-128).

Suitably, in an embodiment of the invention and/or embodiments thereof—NR⁶R⁷ is selected from the group consisting of (a-1), (a-3), (a-5),(a-9), (a-20), (a-34), (a-35), (a-36), (a-42), (a-46), (a-55), (a-64),and (a-65).

Suitably, in an embodiment of the invention and/or embodiments thereofNR⁶R⁷ is selected from the group consisting of (a-1), (a-3), (a-5),(a-20), (a-34), (a-35), (a-36), (a-46), (a-55), and (a-65).

Suitably in an embodiment of the invention and/or embodiments thereof,when R⁶ is H then R⁷ is not H.

In embodiments, L is selected from the group consisting of

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, aryl,        heterocyclyl, heteroaryl,        —(NR^(L3))₀₋₁—(CH₂)₀₋₄—NR^(L3)—(CH₂)₀₋₄—,        —(NR^(L3))₀₋₁(CR^(L1)R^(L2))₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—,        —(CR^(L1)R^(L2))₀₋₄—O—(CR^(L1)R^(L2))—,        —(CH₂)₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—C(═O)NH—(CH₂)₀₋₄—,        —C(═O)—(CR^(L1)R^(L2))—NR^(L3)C(═O)—, —C(═O)NR^(L3)—,        —NR^(L3)C(═O)—, —NR^(L3)—, —SO₂NR^(L3)—, —NR^(L3)—C(═O)—NR^(L3)—    -   wherein        -   R^(L1), R^(L2), R^(L3), are independently selected from the            group consisting of        -   H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with            aryl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl            substituted with heterocyclyl; or        -   R^(L1), R^(L3) together with the atoms to which they are            attached can form a saturated or unsaturated heterocyclic            ring having 3 to 8 ring atoms, wherein 1, 2, or 3, ring            atoms are selected from N, S, and O.

In embodiments, L is selected from the group consisting of

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        —(NR^(L3))₀₋₁—(CH₂)₀₋₄—NR^(L3)—(CH₂)₀₋₄—,        —(NR^(L3))₀₋₁—(CR^(L1)R^(L2))₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—,        —(CR^(L1)R^(L2))₀₋₄—O—(CR^(L1)R^(L2))—,        —(CH₂)₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—C(═O)NH—(CH₂)₀₋₄—,        —C(═O)—(CR^(L1)R^(L2))—NR^(L3)C(═O)—, —C(═O)NR^(L3)—,        —NR^(L3)C(═O)—, —NR^(L3)—, —SO₂NR^(L3)—, NR^(L3)—C(═O)—NR^(L3)—    -   wherein        -   R^(L1), R^(L2), R^(L3), are independently selected from the            group consisting of    -   H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with        aryl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl        substituted with heterocyclyl; or    -   R^(L1), R^(L3) together with the atoms to which they are        attached can form a saturated or unsaturated heterocyclic ring        having 3 to 8 ring atoms, wherein 1, 2, or 3, ring atoms are        selected from N, S, and O.

In embodiments, L is selected from the group consisting of

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        —(NR^(L3))₀₋₁—(CH₂)₀₋₄—NR^(L3)—(CH₂)₀₋₄—,        —(NR^(L3))₀₋₁—(CR^(L1)R^(L2))₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—,        —(CR^(L1)R^(L2))₀₋₄—O—(CR^(L1)R^(L2))—, —NR^(L3)—, —SO₂NR^(L3)—,    -   wherein        -   R^(L1), R^(L2), R^(L3), are independently selected from the            group consisting of    -   H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with        aryl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl        substituted with heterocyclyl; or    -   R^(L1), R^(L3) together with the atoms to which they are        attached can form a saturated or unsaturated heterocyclic ring        having 3 to 8 ring atoms, wherein 1, 2, or 3, ring atoms are        selected from N, S, and O.

In embodiments, L is selected from the group consisting of

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,        —NR^(L3)—,    -   wherein        -   R^(L3), is selected from the group consisting of        -   H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with            aryl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl            substituted with heterocyclyl.

Suitably L is selected from the group consisting of C₁₋₆-alkyl, orC₂₋₆-alkenyl.

Suitably L is C₁₋₆-alkyl. Suitably L is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—. Suitably L is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. SuitablyL is —CH₂—, or —CH₂CH₂—.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (VIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments, M is selected from the group consisting of

-   -   C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl, C₂₋₄alkenyl,        C₂₋₄alkynyl, —C(R^(M1))═C(R^(M1))═C≡C—, —C(R^(M1))═C(R^(M1))—,    -   wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is        optionally substituted with a substituent selected from the        group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(M2)R^(M3),            carbonyl, —C(═O)—OR^(M2), halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl            substituted with aryl, cyano, hydroxy, —SR^(M2), —SO₂R^(M4),            —OSO₂R^(M4), —SO₂NR^(M2)R^(M3), —C(═O)NR^(M2)R^(M3)—,            hydroxy-C₁₋₆-alkyl;    -   wherein R^(M1) is selected from the group consisting of H,        C₁₋₆-alkyl, halo, hydroxyl, and amino;    -   wherein R^(M2), R^(M3) are independently selected from the group        consisting of H, and C₁₋₆-alkyl;    -   wherein R^(M4) is selected from the group consisting of H,        C₁₋₆-alkyl, and amino.

In some embodiments, M is selected from the group consisting of

-   -   C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl, C₂₋₄alkenyl,        C₂₋₄alkynyl, —C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—.

Suitably M is selected from the group consisting of

-   -   aryl, heterocyclyl, heteroaryl, —C(R^(M1))═C(R^(M1))—C≡C—,        —C(R^(M1))═C(R^(M1))—.

Suitably M is selected from the group consisting of

-   -   aryl, heteroaryl, —C(R^(M1))═C(R^(M1))—C≡C—,        —C(R^(M1))═C(R^(M1))—.

Suitably M is selected from the group consisting of

-   -   aryl, and heteroaryl.

Suitably M is selected from the group consisting of

-   -   phenyl, thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furanyl,        pyrrolyl, imidazolyl, oxazolyl, pyrazinyl, pyranyl, thiopyranyl,        oxazinyl, thiazynyl, —C(R^(M1))═C(R^(M1))—C≡C—,        —C(R^(M1))═C(R^(M1))

Suitably M is selected from the group consisting of

-   -   phenyl, thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furanyl,        pyrrolyl, imidazolyl, oxazolyl, pyrazinyl,        —C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—.

Suitably M is selected from the group consisting of

-   -   phenyl, thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furanyl,        —C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—.

Suitably M is selected from the group consisting of

-   -   phenyl, thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furanyl,        —C(H)═C(H)—C≡C—, —C(H)═C(H)—.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of M isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, C₁₋₆-alkyloxy, NR^(M2)R^(M3), carbonyl,        —C(═O)—OR^(M2), halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, cyano, hydroxy, —SR^(M2),        —SO₂R^(M4), —OSO₂R^(M4), —SO₂NR^(M2)R^(M3),        —C(═O)NR^(M2)R^(M3)—, hydroxy-C₁₋₆-alkyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of M isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, C₁₋₆-alkyloxy, NR^(M2)R^(M3), carbonyl,        —C(═O)OR^(M2), halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, cyano, hydroxy, —SR^(M2),        —SO₂R^(M4), —OSO₂R^(M4), —SO₂NR^(M2)R^(M3),        —C(═O)NR^(M2)R^(M3)—, hydroxy-C₁₋₆-alkyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of M isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, halo, amino, halo-C₁₋₆-alkyl,        C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with aryl,        cyano, hydroxy, —SR^(M2), —SO₂R^(M4), —OSO₂R^(M4),        —SO₂NR^(M2)R^(M3), hydroxy-C₁₋₆-alkyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of M isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, halo, halo-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl.

Suitably R^(M1) is selected from the group consisting of H, C₁₋₆-alkyl,halo, hydroxyl, and amino. Suitably R^(M1) is selected from the groupconsisting of H, C₁₋₆-alkyl, and halo. Suitably R^(M1) is selected fromthe group consisting of H, and C₁₋₆-alkyl.

Suitably, R^(M2), R^(M3) are independently selected from the groupconsisting of H, and C₁₋₆-alkyl.

Suitably R^(M4) is selected from the group consisting of H, C₁₋₆-alkyl,and amino. Suitably R^(M4) is selected from the group consisting of H,and C₁₋₆-alkyl.

Particular suitable groups of M are selected from the group consistingof

Particular suitable groups of M are selected from the group consistingof (m-1), (m-3), (m-5), (m-8), (m-14), (m-15), (m-16), (m-17).

Particular suitable groups of M are selected from the group consistingof (m-1), (m-8), (m-16).

In another embodiment of the invention and/or embodiments thereof G isselected from the group consisting of

-   -   —(C(R^(G2)R^(G3))₀₋₄—O—(C(R^(G2)R^(G3))₀₋₄—,        —(C(R^(G2)R^(G3))₀₋₄—S—(C(R^(G2)R^(G3))₀₋₄—,        —(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—, —C(═O)—,        —NR^(G1)C(═O)—, —C(═O)NR^(G1)—,        —(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—C(R^(G2)R^(G3))—C(═O)NR^(G1)—,        —CR^(G2)═CR^(G2)—, —CR^(G2)═CR^(G2)—CR^(G2)═CR^(G2)—, —C≡C—,        —C≡C—C≡C—, —CR^(G2)═CR^(G2)—C═C, —C═C—CR^(G2)═CR^(G2),        —C(═O)—C═C—, —C═C—C(═O)— —SO₂—, —S(═O)—, —S(═O)C(R^(G2)R^(G3))—.        —C(R^(G2)R^(G3))S(═O)—, —C(R^(G2)R^(G3))—SO₂—,        —SO₂C(R^(G2)R^(G3))—;    -   wherein        -   R^(G1) is H or C₁₋₆-alkyl        -   each R^(G2), R^(G3) is independently selected from the group            consisting of H, halogen atom, or C₁₋₆-alkyl.

In suitable embodiments, G is selected from the group consisting of—(C(R^(G2)R^(G3))₀₋₄—O—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—S—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—, —C(═O)—,—NR^(G1)C(═O)—, —C(═O)NR^(G1)—,—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—C(R^(G2)R^(G3))—C(═O)NR^(G1)—,—CR^(G2)═CR^(G2)—, —C≡C—, —C≡C—C≡C—, —C≡C—C(═O)— —SO₂—, —S(═O)—,—S(═O)C(R^(G2)R^(G3))—. —C(R^(G2)R^(G3))S(═O)—, —C(R^(G2)R^(G3))—SO₂—,—SO₂C(R^(G2)R^(G3))—;

-   -   wherein        -   R^(G1) is H or C₁₋₆-alkyl        -   each R^(G2), R^(G3) is independently selected from the group            consisting of H, halogen atom, or C₁₋₆-alkyl.

Suitably G is selected from the group consisting of CR^(G2)═CR^(G2)—,—CR^(G2)═CR^(G2)—CR^(G2)═CR^(G2)—, —C≡C—, —C≡C—C≡C—,—CR^(G2)═CR^(G2)—C≡C—, —C≡C—CR^(G2)═CR^(G2), —C(═O)—C≡C—, —C≡C—C(═O)—,wherein R^(G2) is selected from the group consisting of H, halogen atom,or C₁₋₆-alkyl.

In suitable embodiments, G is selected from the group consisting of—C≡C—, —C≡C—C≡C—, —CR^(G2)═CR^(G2)—C≡C—, —C≡C—CR^(G2)═CR^(G2), whereinR^(G2) is selected from the group consisting of H, halogen atom, orC₁₋₆-alkyl.

In another suitable embodiments, G is selected from the group consistingof CR^(G2)═CR^(G2)—, —C≡C—, —C≡C—C≡C—, —C≡C—C(═O)—.

-   -   wherein        -   R^(G2) is selected from the group consisting of        -   H, halogen atom, or C₁₋₆-alkyl.

In another suitable embodiments, G is selected from the group consistingof —C≡C—, —C≡C—C≡C—.

In another suitable embodiments, G is —C≡C—.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (II)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, Y, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (IX)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, Y, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (X)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, Y, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (XI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (XIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompound is a compound according to formula (XIV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are definedas in any of the embodiments described herein.

In embodiments of the invention and embodiments thereof, Y is selectedfrom the group consisting of

-   -   C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl,    -   wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is        optionally substituted with a substituent selected from the        group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(Y1)R^(Y2),            carbonyl, —C(═O)—OR^(Y1), halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl            substituted with aryl, cyano, hydroxy, —SR^(Y2), —SO₂R^(Y3),            —OSO₂R^(Y3), —SO₂NR^(Y1)R^(Y2), —C(═O)NR^(Y1)R^(Y2)—,            hydroxy-C₁₋₆-alkyl;    -   wherein R^(Y1), R^(Y2) are independently selected from the group        consisting of H, and C₁₋₆-alkyl;    -   wherein R^(Y3) is selected from the group consisting of H,        C₁₋₆-alkyl, and amino.

In embodiments of the invention and/or embodiments thereof, Y isselected from

-   -   aryl, or heteroaryl.

Suitably Y is aryl. Suitably Y is phenyl. Suitably Y is para-phenyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of Y isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, C₁₋₆-alkyloxy, NR^(Y1)R^(Y2), carbonyl,        —C(═O)—OR^(Y1), halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, cyano, hydroxy, —SR^(Y2),        —SO₂R^(Y3), —OSO₂R^(Y3), —SO₂NR^(Y1)R^(Y2),        —C(═O)NR^(Y1)R^(Y2)—, hydroxy-C₁₋₆-alkyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of Y isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, C₁₋₆-alkyloxy, NR^(Y1)R^(Y2), carbonyl,        —C(═O)—OR^(Y1), halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl,        C₁-C₆-alkyl substituted with aryl, cyano, hydroxy, —SR^(Y2),        —SO₂R^(Y3), —OSO₂R^(Y3), —SO₂NR^(Y1)R^(Y2),        —C(═O)NR^(Y1)R^(Y2)—, hydroxy-C₁₋₆-alkyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of Y isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, NR^(Y1)R^(Y2), halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with aryl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl.

Suitably the cycloalkyl, aryl, heterocyclyl, or heteroaryl of Y isoptionally substituted with a substituent selected from the groupconsisting of

-   -   C₁₋₆-alkyl, halo, halo-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl.

Suitably, the cycloalkyl, aryl, heterocyclyl, or heteroaryl of Y is notsubstituted.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XVI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In embodiments of the invention and embodiments thereof, X is selectedfrom the group consisting of

-   -   —C(═O)—, —C₁₋₆-alkyl-C(═O)—, —C₂₋₆-alkenyl-C(═O)—,        —C₂₋₆-alkynyl-C(═O)—, and —(C(R^(X1))₂—, —S(═O)—, —SO₂—;    -   wherein        -   R^(X1), R^(X2), is selected from the group consisting of H,            halogen atom, substituted C₁₋₆-alkyl, or un-substituted            C₁₋₆-alkyl;        -   wherein the substituents on the substituted C₁₋₆-alkyl may            be selected from the group consisting of halogen, hydroxyl,            alkoxy, aryloxy, ester, thiol, C₁₋₆-alkyl, carbonyl,            —SR^(X3), —SO₂R^(X5), —C(═O)NR^(X3)R^(X4), cyano,            —NR^(X3)R^(X4), —C(═O)—OR^(X3), aryl, heteroaryl,            heterocycle, C₃₋₈-cycloalkyl;        -   wherein R^(X3), R^(X4) are independently selected from the            group consisting of H, or C₁₋₆-alkyl; wherein R^(X5) is            selected from the group consisting of H, C₁₋₆-alkyl, and            amine.

Suitably X is selected from the group consisting of —C(═O)—,—C₁₋₆-alkyl-C(═O)—, S(═O)—, —SO₂—. Suitably X is selected from —C(═O)—,and S(═O)—.

Suitably R^(X1), R^(X2), are independently selected from the groupconsisting of H, halogen atom, substituted C₁₋₆-alkyl, or un-substitutedC₁₋₆-alkyl;

-   -   wherein the substituents on the substituted C₁₋₆-alkyl may be        selected from the group consisting of halogen, hydroxyl, alkoxy,        carbonyl, —SR^(X3), —SO₂R^(X5), —C(═O)NR^(X3)R^(X4), cyano,        —NR^(X3)R^(X4), —C(═O)—OR^(X3).

Suitably the substituents on the substituted C₁₋₆-alkyl of X is selectedfrom the group consisting of halogen, hydroxyl, carbonyl, —SR^(X3),—SO₂R^(X5), —C(═O)NR^(X3)R^(X4), —NR^(X3)R^(X4).

Suitably the substituents on the substituted C₁₋₆-alkyl of X is selectedfrom the group consisting of halogen or amino.

Suitably R^(X1), R^(X2), are independently selected from the groupconsisting of H, halogen atom, or un-substituted C₁₋₆-alkyl.

Suitably, R^(X3), R^(X4) are independently selected from the groupconsisting of H, or C₁₋₆-alkyl; Suitably R^(X5) is selected from thegroup consisting of H, C₁₋₆-alkyl, and amine.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (IV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XVII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XVIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XIX)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XX)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, Y, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In suitable embodiments of the invention and/or embodiments thereof R⁵is selected from the group consisting of H, and C₁₋₆-alkyl. Suitably R⁵is H.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R¹, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In embodiments of the invention and/or embodiments thereof R², R³ isindependently selected from the group consisting of

-   -   H, substituted C₁₋₆-alkyl, or un-substituted C₁₋₆-alkyl;        -   wherein the substituents on the substituted C₁₋₆-alkyl may            be selected from the group consisting of halogen, hydroxyl,            alkoxy, aryloxy, ester, thiol, C₁₋₆-alkyl, carbonyl, —SR⁸,            —SO₂R³, —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, cyano, —NR⁹R¹⁰,            —C(═O)—OR⁹, aryl, heteroaryl, heterocycle, C₃₋₈-cycloalkyl.

Suitably R², R³ is independently selected from the group consisting ofH, substituted C₁₋₆-alkyl, or un-substituted C₁₋₆-alkyl. Suitably R² andR³ are H.

In some embodiment, the substituents on the substituted C₁₋₆-alkyl of R²and/or R³ may be selected from the group consisting of hydroxyl, alkoxy,aryloxy, ester, thiol, C₁₋₆-alkyl, carbonyl, —SR³, —SO₂R⁸, —SO₂NR⁹R¹⁰,—C(═O)NR⁹R¹⁰, cyano, —NR⁹R¹⁰, —C(═O)—OR⁹, aryl, heteroaryl, heterocycle,C₃₋₈-cycloalkyl.

In some embodiment, the substituents on the substituted C₁₋₆-alkyl of R²and/or R³ may be selected from the group consisting of hydroxyl,C₁₋₆-alkyl, carbonyl, —SR⁸, —SO₂NR⁹R¹⁰, —SO₂R⁸, —C(═O)NR⁹R¹⁰, cyano,—NR⁹R¹⁰, —C(═O)—OR⁹.

R⁸ is selected from the group consisting of H, C₁₋₆-alkyl, and amine.

R⁹, R¹⁰ are independently selected from the group consisting of H, andC₁₋₆-alkyl.

In some embodiment, the substituents on the substituted C₁₋₆-alkyl of R²and/or R³ may be selected from the group consisting of hydroxyl,C₁₋₆-alkyl, —NR⁹R¹⁰.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R¹, R², R⁵, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In embodiments of the invention and/or embodiments thereof R⁴ isselected from the group consisting of H, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, —OR⁸, C(═O)OR⁸, C(═O)R⁸, aryl,heterocyclyl, heteroaryl, C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkylsubstituted with heteroaryl, C₁-C₆-alkyl substituted with heterocyclyl

-   -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl, heteroaryl, is optionally substituted with a        substituent selected from the group consisting of        -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR⁹R¹⁰,            carbonyl, nitro, C(═O)OR⁹, halogen, halo-C₁₋₆-alkyl,            C₁₋₆-alkyloxy-C₁₋₆-alkyl, cyano, hydroxy, —SR⁸, —SO₂R⁸,            —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰.

In embodiments of the invention and/or embodiments thereof R⁴ isselected from the group consisting of H, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, —OR⁹, C(═O)OR⁹, C(═O)R⁹, C₁-C₆-alkyl substituted witharyl, C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl substitutedwith heterocyclyl.

In embodiments of the invention and/or embodiments thereof R⁴ isselected from the group consisting of H, C₁₋₆-alkyl, —OR⁹, C(═O)OR⁹,C(═O)R⁹.

In embodiments of the invention and/or embodiments thereof R⁴ isselected from the group consisting of H, —OR⁹. Suitably R⁴ is —OR⁹, moresuitably R⁹ is OH.

In embodiments of the invention and/or embodiments thereof the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, of R⁴ isoptionally substituted with a substituent selected from the groupconsisting of C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR⁹R¹⁰,carbonyl, nitro, C(═O)OR⁹, halogen, halo-C₁₋₆-alkyl,C₁₋₆-alkyloxy-C₁₋₆-alkyl, cyano, hydroxy, —SR⁸, —SO₂R¹, —SO₂NR⁹R¹⁰,—C(═O)NR⁹R¹⁰.

In embodiments of the invention and/or embodiments thereof the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, of R⁴ isoptionally substituted with a substituent selected from the groupconsisting of C₁₋₆-alkyl, C₃₋₈-cycloalkyl, NR⁹R¹⁰, carbonyl, nitro,halogen, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl, cyano, hydroxy.

In embodiments of the invention and/or embodiments thereof the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, of R⁴ isoptionally substituted with a substituent selected from the groupconsisting of C₁₋₆-alkyl, NR⁹R¹⁰, halogen, cyano, hydroxy.

In embodiments of the invention and/or embodiments thereof the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, of R⁴ isoptionally substituted with a substituent selected from the groupconsisting of C₁₋₆-alkyl, NR⁹R¹⁰, halogen.

In embodiments of the invention and/or embodiments thereof R⁸ isselected from the group consisting of H, C₁₋₆-alkyl, and amine. SuitablyR⁸ is H or C₁₋₆-alkyl.

In embodiments of the invention and/or embodiments thereof R⁹, R¹⁰ areindependently selected from the group consisting of H, and C₁₋₆-alkyl.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXIV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXVI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXVII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXVIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXIX)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXX)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXIV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXVI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXVII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXVIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XXXIX)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XL)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLIV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLV)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLVI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLVII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, X, R², R³, R⁴, R⁶, and R⁷, aredefined as in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLVIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein L, M, G, Y, R², R³, R⁴, R⁶, and R⁷, are definedas in any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (XLIX)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein M, G, Y, R², R³, R⁴, R⁶, and R⁷, are defined asin any of the embodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (L)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein R⁶, and R⁷, are defined as in any of theembodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (LI)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein R⁶, and R⁷, are defined as in any of theembodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (LII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein R⁶, and R⁷, are defined as in any of theembodiments described herein.

In some embodiments of the invention and/or embodiments thereof thecompounds are compounds according to formula (LIII)

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein R⁶, and R⁷, are defined as in any of theembodiments described herein.

The invention is also directed to method for treating an animal with aninfection by a bacteria comprising administering to the subject in needthereof an effective amount of a compound of the present inventionand/or embodiments thereof with a pharmaceutically acceptable carrier,wherein the bacteria is at least one of the bacteria selected from thegroup Mannheimia haemolytica and Histophilus somni. Suitably the subjectis a mammal and in some embodiments, a ruminant or swine.

Further the invention is directed to a compound according to the presentinvention and/or embodiments thereof with a pharmaceutically acceptablecarrier for use in the treatment of a infection by a bacteria in asubject, wherein the bacteria is at least one of the bacteria selectedfrom the group Mannheimia haemolytica and Histophilus somni. Suitablythe subject is a mammal and in some embodiments, a ruminant or swine.

The invention provides further a pharmaceutical composition comprisingan effective amount of a compound according to the invention and/orembodiments thereof with a pharmaceutically acceptable carrier thereof.

Suitably the compound of the present invention and/or embodimentsthereof, is co-administered with other therapeutic agents that areselected for their particular usefulness against the condition that isbeing treated.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

The compound of the present invention and/or embodiments thereof mayalso be used in the treatment of Bovine Respiratory Disease and/or SwineRespiratory disease.

Pharmaceutical Compositions

Pharmaceutical compositions of the present invention and/or embodimentsthereof comprise a therapeutically effective amount of a compound of thepresent invention and/or embodiments thereof formulated together withone or more pharmaceutically acceptable carriers.

As used herein, the term “pharmaceutically acceptable carrier” means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials that can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The pharmaceuticalcompositions of this invention and/or embodiments thereof can beadministered to animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray, ora liquid aerosol or dry powder formulation for inhalation.

The term “pharmaceutically acceptable salt” includes a salt with aninorganic base, organic base, inorganic acid, organic acid, or basic oracidic amino acid.

Examples of often suitable inorganic acids for making (pharmaceuticallyacceptable) salts include hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric, and phosphoric acid. Examples of often suitableorganic acids for making (pharmaceutically acceptable) salts generallyinclude, for example, aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids.Specific examples of often suitable organic acids include cholic,sorbic, lauric, acetic, trifluoroacetic, formic, propionic, succinic,glycolic, gluconic, digluconic, lactic, malic, tartaric acid, citric,ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, arylcarboxylic acid (e.g., benzoic), anthranilic acid, mesylic, stearic,salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),alkylsulfonic (e.g., ethanesulfonic), arylsulfonic (e.g.,benzenesulfonic), pantothenic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, p-hydroxybutyric, galactaric, galacturonic,adipic, alginic, butyric, camphoric, camphorsulfonic,cyclopentanepropionic, dodecylsulfic, glycoheptanoic, glycerophosphic,heptanoic, hexanoic, nicotinic, 2-naphthalesulfonic, oxalic, palmoic,pectinic, 3-phenylpropionic, picric, pivalic, thiocyanic, tosylic, andundecanoic acid. In some such embodiments, for example, the saltcomprises a trifluoroacetate, mesylate, or tosylate salt. In otherembodiments, the salt comprises a hydrochloric acid salt. In general, abase addition salt can be prepared by reacting a free acid compound withan approximately stoichiometric amount of an inorganic or organic base.Examples of base addition salts may include, for example, metallic saltsand organic salts. Metallic salts, for example, include alkali metal(group Ia) salts, alkaline earth metal (group IIa) salts, and otherphysiologically acceptable metal salts. Such salts may be made fromaluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Forexample, a free acid compound may be mixed with sodium hydroxide to formsuch a base addition salt. Organic salts may be made from amines, suchas trimethylamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, ethanolamine, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as C₁-C₆-alkyl halides (e.g., methyl,ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkylsulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), longchain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides,bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethylbromides), and others.

As salts of basic amino acids, the instant invention includes, forexample, arginine, lysine and ornithine. Acidic amino acids include, forexample, aspartic acid and glutamic acid.

The term “pharmaceutically acceptable ester” refers to esters thathydrolyze in vivo and include those that break down readily in the humanbody to leave the parent compound or a salt thereof. Suitable estergroups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Representativeexamples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrug” as used herein refers tothose prodrugs of the compounds of the present invention that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “antibacterial agent” refers to agents synthesized or modifiedin the laboratory that have either bactericidal or bacteriostaticactivity. An “active” agent in this context will inhibit the growth ofP. aeruginosa and other gram-negative bacteria. The term “inhibiting thegrowth” indicates that the rate of increase in the numbers of apopulation of a particular bacterium is reduced. Thus, the term includessituations in which the bacterial population increases but at a reducedrate, as well as situations where the growth of the population isstopped, as well as situations where the numbers of the bacteria in thepopulation are reduced or the population even eliminated. If an enzymeactivity assay is used to screen for inhibitors, one can makemodifications in uptake/efflux, solubility, half-life, etc. to compoundsin order to correlate enzyme inhibition with growth inhibition. Theactivity of antibacterial agents is not necessarily limited to bacteriabut may also encompass activity against parasites, virus, and fungi.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U. S. P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionthat, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly (orthoesters) and poly (anhydrides). Depot injectableformulations may also be prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration can be prepared bymixing the compounds of this invention with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum or vaginal cavity andrelease the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid; b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,acetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient (s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient (s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulations, ear drops, and the like are also contemplatedas being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Compositions of the invention may also be formulated for delivery as aliquid aerosol or inhalable dry powder. Liquid aerosol formulations maybe nebulized predominantly into particle sizes that can be delivered tothe terminal and respiratory bronchioles where bacteria reside inpatients with bronchial infections, such as chronic bronchitis andpneumonia. Pathogenic bacteria are commonly present throughout airwaysdown to bronchi, bronchioli and lung parenchema, particularly interminal and respiratory bronchioles. During exacerbation of infection,bacteria can also be present in alveoli.

Liquid aerosol and inhalable dry powder formulations are preferablydelivered throughout the endobronchial tree to the terminal bronchiolesand eventually to the parenchymal tissue.

Aerosolized formulations of the invention may be delivered using anaerosol forming device, such as a jet, vibrating porous plate orultrasonic nebulizer, preferably selected to allow the formation of aaerosol particles having with a mass medium average diameterpredominantly between 1 to 5 pm.

Further, the formulation preferably has balanced osmolarity ionicstrength and chloride concentration, and the smallest aerosolizablevolume able to deliver effective dose of the compounds of the inventionto the site of the infection. Additionally, the aerosolized formulationpreferably does not impair negatively the functionality of the airwaysand does not cause undesirable side effects.

Aerosolization devices suitable for administration of aerosolformulations of the invention include, for example, jet, vibratingporous plate, ultrasonic nebulizers and energized dry powder inhalers,that are able to nebulize the formulation of the invention into aerosolparticle size predominantly in the size range from 1-5 um. Predominantlyin this application means that at least 70% but preferably more than 90%of all generated aerosol particles are 1 to 5 pm range. A jet nebulizerworks by air pressure to break a liquid solution into aerosol droplets.Vibrating porous plate nebulizers work by using a sonic vacuum producedby a rapidly vibrating porous plate to extrude a solvent droplet througha porous plate. An ultrasonic nebulizer works by a piezoelectric crystalthat shears a liquid into small aerosol droplets.

Compounds of the invention may also be formulated for use as topicalpowders and sprays that can contain, in addition to the compounds ofthis invention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances.

Sprays can additionally contain customary propellants such aschlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin.

The rate can be controlled by either providing a rate controllingmembrane or by dispersing the compound in a polymer matrix or gel.

According to the treatment by the compounds of the present inventionand/or embodiments thereof, bacterial infections are treated orprevented in an animal by administering to the animal a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionand/or embodiments thereof is meant a sufficient amount of the compoundto treat bacterial infections, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician orveterinary doctor within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular animalwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the animal; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts.

Methods of formulation are well known in the art and are disclosed, forexample, in Remington: The Science and Practice of Pharmacy, MackPublishing Company, Easton, Pa., 19th Edition (1995). Pharmaceuticalcompositions for use in the present invention can be in the form ofsterile, non-pyrogenic liquid solutions or suspensions, coated capsules,suppositories, lyophilized powders, transdermal patches or other formsknown in the art.

A “kit” as used in the instant application includes a container forcontaining the pharmaceutical compositions and may also include dividedcontainers such as a divided bottle or a divided foil packet.

The container can be in any conventional shape or form as known in theart that is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, a resealablebag (for example, to hold a “refill” of tablets for placement into adifferent container), or a blister pack with individual doses forpressing out of the pack according to a therapeutic schedule.

The container employed can depend on the exact dosage form involved, forexample a conventional cardboard box would not generally be used to holda liquid suspension. It is feasible that more than one container can beused together in a single package to market a single dosage form. Forexample, tablets may be contained in a bottle that is in turn containedwithin a box.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of individual tabletsor capsules to be packed or may have the size and shape to accommodatemultiple tablets and/or capsules to be packed. Next, the tablets orcapsules are placed in the recesses accordingly and the sheet ofrelatively stiff material is sealed against the plastic foil at the faceof the foil that is opposite from the direction in which the recesseswere formed. As a result, the tablets or capsules are individuallysealed or collectively sealed, as desired, in the recesses between theplastic foil and the sheet. Preferably the strength of the sheet is suchthat the tablets or capsules can be removed from the blister pack bymanually applying pressure on the recesses whereby an opening is formedin the sheet at the place of the recess. The tablet or capsule can thenbe removed via said opening.

Compositions of the present compounds may also be used in combinationwith other known antibacterial agents of similar spectrum to (1)synergistically enhance treatment of severe Gram-negative infectionscovered by the spectrum of this compound or (2) add coverage in severeinfections in which multiple organisms are suspected in which anotheragent of a different spectrum may be required in addition to thiscompound. Potential agents include members of the aminoglycosides,penicillins, cephalosporins, fluoroquinolones, macrolides,glycopeptides, lipopeptides and oxazolidinones. The treatment caninvolve administering a composition having both active agents oradministration of the inventive compounds followed by or preceded byadministration of an additional active antibacterial agent. Types ofanimals that may benefit from the practice of the invention include anythat are susceptible to infection by an etiological agent of Bovinerespiratory Disease (BRD) or alternatively, swine respiratory disease(SRD).

Exemplary animals include but are not limited to: members of thebiological subfamily Bovinae which includes medium- to large-sizedungulates such as domestic dairy and beef cattle, bison, Africanbuffalo, the water buffalo, etc. The animals may be so-called livestockraised in an agricultural setting for the production of dairy productsor meat; or may be raised to perform work; or may be in another setting,e.g. in a zoo, animal reserve, etc., or raised for some other reason,e.g. as pets, show animals, for breeding purposes, etc.

Especially preferred is the use of the compounds of the currentinvention in beef cattle. Beef cattle are cattle raised for meatproduction (as distinguished from dairy cattle, used for milkproduction). There are three main stages in beef production: cow-calfoperations, backgrounding, and feedlot operations. Especially preferredis the use of the compounds of the current invention in feedlotoperations. The compounds of the invention can be used in beef (anddairy) cattle of every age, in calf, heifers, steer, cows. The compoundof the invention can be used in animals of different weight, includingheavy animals of a weight higher than 350 kg.

Other exemplary animals that can be treated with the compounds andcompositions of the current invention are small ruminants, such a sheepor goats or pseudoruminants, such as e.g. camels or lamas. In oneembodiment the compounds of the current invention is used to treatrespiratory diseases such as enzootic pneumonia of lambs and/or adultsheep (ewes, rams) that are kept for meat or as breeding stock. Enzooticpneumonia is an acute infectious disease of sheep characterised byfever, nasal discharge, pneumonitis and pleuritis.

The compounds of the current invention can be alternatively used totreat Swine respiratory disease (SRD), that is a disease of animals ofthe family Suidae. Suidae are commonly called pigs, swine, hogs, orboars. The compounds of the current invention can be administered ingeneral to all swine animals; to sucker, weaner, boars, barrows, giltsor sows. It can be used in one or more of the phases of swine farmingfor meat: suckling pigs, feeder pigs, grower, and finisher pigs or inbackfatter pigs. Alternatively it can be used in breeding stocks, i.e.in breeding sows, gilts or boars or the offspring of such animal asreplacement breeding stock.

In one embodiment, the animal that is treated is a bovine animal and thedisease that is treated is BRD. In another embodiment the animal is asuidae (porcine) animal and the disease that is treated is SRD. Thecompounds of the current invention can be used to treat diseased animalsthat display clinical symptoms of Bovine Respiratory disease or Swinerespiratory disease.

The compounds of the current invention can additionally or alternativelybe used to treat animals with subclinical infections with Pasteurellaspp., Mannheimia spp., and Histophilus spp. infections. A subclinicalinfection is nearly or completely asymptomatic (no disease signs orsymptoms). Therefore identifying affected animals early in the course ofBRD or SRD is difficult and subclinical infection is mainly detected atthe slaughterhouse when checking the lungs for lesions. However,subclinical BRD or SRD infection result in lower average daily gains(ADG).

In addition to treatment purposes, the compositions and methods of theinvention are also suitable for metaphylactic use. For example, in caseof an outbreak of Bovine Respiratory disease or Swine respiratorydisease, administration of the compounds of the current invention tonon-affected (or subclinical infected) animals, especially those whichare in close contact with those showing clinical signs of disease, couldprevent the spread of the infection.

In addition, prophylactic treatment might be undertaken in bovinesconsidered to be vulnerable to infection and/or in whom infection couldhave grave consequences, e.g. calves, show cattle, pregnant females,prize bulls or boars, etc., whether or not an outbreak of the disease isknown to have occurred. Another option is the prophylacticadministration of compounds according to the current invention inanimals before shipping and other stress inducing events to preventoutbreak of the disease in such animals.

The same concept of prophylactic or metaphylactic treatment, asdescribed in the herein applies to swine animals at risk for SRD.

In some embodiments, one or more, preferably one compound according tothis invention is used to treat an infection by a pathogen that isresistant to one or more other antibacterial agents. In someembodiments, the compound according to this invention is active againsta pathogen, that is resistant to one or more of the followingantibacterials: macrolide antibiotics, aminoglycosides,fluoroquinolones, or cephalosporins, especially one or more selectedgrom the group of tylosin, erythromycin, tildipirosin, timicosin,tulathromycin, gamithromycin, gentamicin, neomycin, enrofloxacin,ciprofloxacindanafloxaxin, oxytetracycline, chlortetracycline,cefquinome, ceftiofur or florfenicol, sulfonamides or penicillin.

The compounds according to this invention may be administered in variousdosage forms. The term “dosage form” means that the compounds accordingto this invention are formulated into a product suitable foradministering to the animal via the envisaged dosage route. Such dosageforms are sometimes referred to herein as formulations or pharmaceuticalcomposition.

Dosage forms useful in the current invention can be liquid, semi-solidor solid dosage forms.

Liquid dosage forms of the compounds are generally solutions,suspensions or emulsions. A solution is a mixture of two or morecomponents that form a single phase that is homogeneous down to themolecular level. A suspension consists of insoluble solid particlesdispersed in a liquid medium, with the solid particles accounting forabout 0.5% to about 30% of the suspension. The liquid may be aqueous,oily, or both. An emulsion is a heterogeneous dispersion of oneimmiscible liquid in another; it relies on an emulsifying agent forstability. A dry powder (or granule) for reconstitution is mixed andreconstituted with a diluent (e.g. water) as a solution, or as asuspension immediately prior to injection. The principal advantage ofthis dosage form is that it overcomes the problem of instability insolution or suspension.

One dosage route (administration route) is the parenteral, especiallyinjection administration (e.g. subcutaneous injection, intravenousinjection, intramuscular injection, etc.). Parenteral formulations anddelivery systems for non-oral routes comprise liquids (e.g. solutions,suspensions, emulsions, and dry powders for reconstitution), semi-solidsand solids (e.g. implants). The majority of implants, that are used inveterinary medicine, are compressed tablets or dispersed matrix systemsin which the drug is uniformly dispersed within a nondegradable polymeror alternatively extrusion products. In one embodiment the compounds ofthe current invention are administered subcutaneously.

Another possible dosage route is the oral dosage route, wherein thecompound according to this invention is administered via the mouth. Oraldosage forms suitable for oral administration comprise liquids (e.g.injectable, drench, in-feed or drinking water formulations), semi-solids(e.g. pastes, gels), and solids (e.g. tablets, capsules, powders,granules, chewable treats, premixes and medicated blocks).

A drench is a liquid oral formulation that is administered directly intothe mouth/throat of an animal, especially a livestock animal, by meansof a “drench gun” or syringe or another suitable device. When thecomposition is administered in the animal recipient's drinking water oras a drench, it may be convenient to use a solution or suspensionformulation. This formulation can be, for example, a concentratedsuspension that is mixed with water or a dry preparation that is mixedand suspended in the water.

Semi-solid oral formulations (pastes or gels) are generally administeredvia an applicator directly into the mouth of an animal or mixed with thefeed.

Solid oral formulations are either administered directly to an animal(tablet, capsule) or mixed with the feed or via medicated feed blocks.

When the oral formulation is administered via a non-human animal's feed,it may, for example, be fed as a discrete feed or as a chewable treat.Alternatively (or additionally), it may, for example, be intimatelydispersed in the animal recipient's regular feed, used as a topdressing, or in the form of solid pellets, paste or liquid that is addedto the finished feed. When the oral formulation is administered as afeed additive, it may be convenient to prepare a “premix” in which theoral formulation is dispersed in a small amount of a liquid or solidcarrier. This “premix” is, in turn, dispersed in the animal's regularfeed using, for example, a conventional mixer.

Several modified-release delivery systems have been developed, that takeadvantage of the unique anatomy of the ruminant forestomach, i.e. forintra-ruminal administration. An intraruminal bolus is a specificformulation for ruminants and pseudo-ruminants (cattle, sheep, goats,buffalos, camelids, deer etc.). It is a veterinary delayed releasedelivery system which remains in the rumeno-reticular sac of a ruminantanimal over an extended period of time and in which the therapeuticallyactive substance has a predictable and delayed release pattern. Suchintraruminal boluses are usually administered using a balling gun oranother suitable device.

It is contemplated that the compounds according to the current inventionmay alternatively be administered topically (e.g., transdermal via aspot-on, pour-on or spray, or alternatively as a nasal spray or byinhalation).

For instance the compounds according to this invention may beadministered topically using a transdermal formulation (i.e. aformulation that passes through the skin). Alternatively the compoundsaccording to this invention may be administered topically via themucosa, e.g. as nasal spray.

Further aspects regarding formulation of drugs and various excipientsare found in, for example, Gennaro, A. R., et al., eds., Remington: TheScience and Practice of Pharmacy (Lippincott Williams & Wilkins, 20thEd., 2000).

In carrying out the method of this invention, a specified compoundaccording to the invention is preferably administered parenterally to aninfected or susceptible animal.

In another embodiment the compound is administered orally (especially incase of SRD).

When the compound according to this invention is administered orally orparenterally by subcutaneous injection, the total dose is generallygreater than about 0.01 mg/kg (i.e., milligram of compound according tothis invention per kilogram body weight of the treated animal). In somesuch embodiments, the total dose is from about 0.01 to about 100 mg/kg,from about 0.01 to about 50 mg/kg, from about 0.1 to about 25 mg/kg, orfrom about 1 to about 20. For BRD or SRD, for example, the dose isgenerally from about 0.5 to about 15 mg/kg, from about 1 to about 10mg/kg. The same dose range may be suitable for other dosage routes. Thedesired dose, however, may be less in some instances where the compoundaccording to this invention is administered intravenously.

The dose used to control Pasteurella multocida, Mannheimia haemolyticaor Histophilus somni infections or especially BRD will vary with thecompound, the severity of the infection, and the age, weight, andcondition of the animal. The total dose required for several daysprotection will generally, however, be in the range of from about 1 toabout 40 mg/kg bodyweight, and preferably will be in the range of fromabout 2.5 to about 35 mg/kg. Similar dosages are administered to pigs totreat SRD. Protection for up to about seven days can be provided by asingle injection; the length of protection will depend upon the dosegiven. The total dose can also be divided into smaller doses given atintervals, such as once daily for two to seven days. Obviously, othersuitable dosage regimens can be constructed.

A single administration of a composition comprising a compound accordingto this invention can be sufficient to treat an infection and toclinically and/or bacteriologically cure BRD or SRD, or at leastdiminish the clinical symptoms in diseased animals; this is called “oneshot” administration. Although the administration of such a “one-shot”single dose is very suitable, it is contemplated that multiple doses canbe used, e.g. two administrations 12-24 hours apart or alternatively,two administrations, 48-72 hours apart.

Factors affecting the preferred dosage may include, for example,infection to be treated, the type (e.g., species and breed), age, size,sex, diet, activity, and condition of the of the infected animal; thedosage route; pharmacological considerations, such as the activity,efficacy, pharmacokinetic, and toxicology profiles of the particularcompound of the invention and the composition administered; and whetherthe compound according to this invention being administered as part of acombination of active ingredients. Thus, the preferred amount of thecompound according to this invention can vary, and, therefore, candeviate from the typical dosages set forth above. Determining suchdosage adjustments is generally within the skill of those in the art.The effective dosage will vary; for example for prophylactic treatmentrelatively low doses would be administered over an extended time.

The compounds of this invention may be formulated for parenteraladministration by methods recognized in the veterinary pharmaceuticalart. Effective injectable compositions containing these compounds may bein either suspension or solution form. In the preparation of suitableformulations it will be recognized that, in general, the watersolubility of the acid addition salts is greater than that of thecorresponding free bases. Similarly, the free bases are more soluble indilute acids or in acidic solutions than in neutral or basic solutions.

In the solution form a compound is dissolved in a physiologicallyacceptable vehicle. Such vehicles comprise a suitable solvent,preservatives such as benzyl alcohol, if needed, and buffers. Usefulsolvents include, for example, water and aqueous alcohols, glycols, andcarbonate esters such as diethyl carbonate.

Injectable suspension compositions employ a liquid suspending medium,with or without adjuvants, as a vehicle. The suspending medium can be,aqueous or non-aqueous, e.g. water, polyethylene glycol, benzyl alcohol,N methyl pyrrolidone, triacetin, inert oils such as vegetable oils orhighly refined mineral oils.

Suitable physiologically acceptable adjuvants are necessary to keep thecompound suspended in suspension compositions. The adjuvants may bechosen from among thickeners such as carboxymethylcellulose,polyvinylpyrrolidone, gelatin, and the alginates. Many surfactants arealso useful as suspending agents. Lecithin, alkylphenol polyethyleneoxide adducts, naphthalenesulfonates, alkylbenzenesulfonates, and thepolyoxyethylene sorbitan esters are useful suspending agents. Manysubstances which affect the hydrophilicity, density, and surface tensionof the liquid suspending medium can assist in making injectablesuspensions in individual cases. For example, silicone antifoams,sorbitol, and sugars can be useful suspending agents. Other conventionalingredients such as preservatives, buffers, surfactats, or thickenerscan be present in the injectable formulation.

The compounds of this invention exhibit unexpectedly high antibacterialactivity against Mannheimia haemolytica and Pasteurella multocida. Forexample, representative compounds were tested against ***, Mannheimiahaemolytica and Pasteurella multocida, using the conventionalbroth-dilution assay. The minimal inhibitory concentrations (MIC's) ofrepresentative compounds against these species are summarized in TableC.

The concentration of the compounds according to this invention in theapplied dosage form may vary widely depending on, for example, thedosage route. In general, the concentration for injectable or oraladministration is from about 1 to about 70% (by weight). In some suchembodiments, for example, the concentration is from about 1 to about 50%(by weight), or from about 10 to about 50% (by weight). In otherembodiments, the concentration is from about 35 to about 65% (byweight), from about 40 to about 60% (by weight), from about 45 to about55% (by weight), or about 50% (by weight).

Preferred concentration in drinking water are from 0.01 to 0.05% weightby volume, particularly 0.01 to 0.025%, and in-feed from 100 to 400 ppm(g/metric ton), particularly 100 to 200 ppm.

In another aspect the present invention thus provides the administrationof a pharmaceutical composition comprising an antibacterial effectiveamount of one or more, preferably one compound according to thisinvention and one or more pharmaceutically acceptable excipients to ananimal, especially a bovine animal or alternatively a porcine animal,especially for the treatment of BRD or SRD.

The formulation type chosen for a dosage form in any instance willdepend upon the particular purpose envisaged and the physical, chemicaland biological properties of the compound according to this invention.

If the compound according to this invention is administered parentallyvia an injection, the concentration of the compound according to thisinvention in the composition/formulation/dosage form preferably issufficient to provide the desired therapeutically effective amount ofthe compound according to this invention in a volume that is acceptablefor parenteral (subcutaneous) administration and allows an injectionvolume of less than 20 ml/per injection site.

In one embodiment the composition of a compound according to theinvention is administered in a non-edible tissue of the animal that isremoved at slaughter and does not enter the human food chain, e.g. inthe ear or at the base of the ear (at the junction of the pinna with thecranium), or behind the ear, e.g. as described in WO1998041207 orWO2003079923, the content of which is incorporated by reference.Injection in alternative animal tissues of food producing animals, thatdo not enter the (human) food chain after slaughtering of the animal arealso envisaged.

Examples of Contemplated Combination Therapies

The methods and pharmaceutical compositions of this invention encompassmethods wherein a compound according to this invention is the soleactive ingredient administered to the recipient animal. It iscontemplated, however, that the methods and pharmaceutical compositionsalso encompass combination therapies wherein a compound is administeredin combination with one or more other pharmaceutically acceptable activeingredients. The other active ingredient(s) may be, for example, one ormore other compounds according to this invention. Alternatively (oradditionally), the other active ingredient(s) may be one or morepharmaceutically acceptable compounds that are not compounds accordingto this invention. The other active ingredient(s) may target the sameand/or different diseases or conditions.

Contemplated active ingredient(s) that may be administered incombination with the compounds of the current invention include, forexample, antibacterials, anti-inflammatories, pharmaceuticallyacceptable anthelmintics, insecticides and acaricides, insect growthregulators, hormones, immunostimulants, dermatological preparations(e.g. antiseptics and disinfectants), and immunobiologicals (e.g.,vaccines and antisera) for disease prevention.

Therefore this invention is also directed to the use as a medicament ofcombinations comprising a) one or more compounds according to thisinvention with b) one or more pharmaceutically acceptable activecompounds which differ in structure from component a). The activecompounds b) are preferably anti-inflammatory compounds, more preferablyselected from the group consisting of non-steroidal anti-inflammatoryagents (NSAID's), such as e.g. flunixin meglumine, meloxicam, carprofen,ketoprofen, phenylbutazone, or Aspirin. In one embodiment one compoundaccording to the invention is combined with flunixin. In anotherembodiment one compound of the invention is combined with meloxicam.Preferably such combination is used to treat BRD in cattle.

Combination means that a compound of the current invention isadministered in a common formulation with the one or morepharmaceutically acceptable active compounds which differ in structure.

Alternativelty the compound according to the invention is administeredto the animal in parallel (not more than approximately 30 minutes apart)from one or more pharmaceutically acceptable active compounds whichdiffer in structure.

In another embodiment the one or more pharmaceutically acceptable activecompounds which differ in structure b) are antibacterials especially oneor more selected grom the group of tylosin, erythromycin, tildipirosin,timicosin, tulathromycin, gamithromycin, gentamicin, neomycin,enrofloxacin, ciprofloxacindanafloxaxin, oxytetracycline,chlortetracycline, cefquinome, ceftiofur or florfenicol, sulfonamides orpenicillin.

Veterinary formulations for use in the present invention may be preparedby mixing the ingredients in the required proportions. The formulationis then packaged into an appropriate container containing single ormultiple doses ready for administration (ready to use—RTU) oralternatively, can be mixed with a diluent before administration.

Features of the invention have been described in embodiments in thepresent application; however for brevity not all combinations of thefeatures are literally described. Combinations of features as describedabove are however expressly considered to be part of the invention.

The invention will now be further described by the following,non-limiting, examples:

SYNTHESIS EXAMPLES Example 1: General Procedure for the Synthesis ofAldehyde Containing Resins

A suspension of N-Fmoc-hydroxylamine 2-chlorotrityl resin (12.0 g, 6.0mmol) in dichloromethane (160 mL) was shaken for 2 hours and drained.The resin was treated with 20% v/v piperidine in DMF (150 mL) for 30minutes, washed with DMF (5×80 mL) and drained completely. In a separateflask, the N-Fmoc-protected amino acid (18.0 mmol), HATU (6.5 g, 17.1mmol) and DIEA (6.3 mL, 36.0 mmol) were dissolved in DMF (50 mL),stirred for three minutes and then added to the resin. After mixingunder an atmosphere of nitrogen for 2 hours, the mixture was drained,washed with DMF (3×80 mL), and again treated with N-Fmoc-protected aminoacid (18.0 mmol), HATU (6.5 g, 17.1 mmol) and DIEA (6.3 mL, 36.0 mmol).Mixing was continued for 2 hours, when the resin was drained, washedwith DMF (5×80 mL) and drained again. The resin then was treated with20% v/v piperidine in DMF (150 mL) for 30 minutes, drained and washedwith DMF (5×80 mL) and drained again. A solution of 4-ethynylbenzoicacid (2.63 g, 18 mmol), HATU (6.5 g, 17.1 mmol) and DIEA (6.3 ml, 36.0mmol) in DMF (50 mL) was then added to the resin and mixing under anatmosphere of nitrogen was continued for 2 hours. The mixture was thendrained, washed with DMF (5×80 mL) and drained. A solution of thehalo-aryl- or halo-heteroarylaldehyde (24.0 mmol) and DIEA (10.5 mL,60.0 mmol) in DMF (150 mL) was purged with a stream of nitrogen for twominutes and added to the resin. After mixing for 5 min, PdCl₂(PPh₃)₂(842 mg, 1.2 mmol) and CuI (571 mg, 3.0 mmol) were added and the mixturewas mixed under an atmosphere of nitrogen for 48 hours. The resin wasdrained, washed with DMF (4×100 mL), DCM (4×100 mL) and dried in vacuoto give the aldehyde containing resin which was used in the next stepswithout further purification.

Using this procedure, the corresponding amino acid-containing aldehyderesins were obtained using Fmoc-N-(S)-Val-OH, Fmoc-N-(S)-Ser(CBu)-OH,Fmoc-N-(S)-Ile-OH, Fmoc-N-3-OTBS-(S)-Val-OH and Fmoc-N-3-MeS-(S)-Val-OH,Fmoc-N-2-amino-3-methoxyimino-(2S)-butanoic acid and(2S)-Fmoc-N-2-amino-2-(2-methyl-1,3-dioxolan-2-yl)acetic acid.

Using this procedure, all aldehyde-containing resins were obtained using4-iodobenzaldehyde, 3-iodobenzaldehyde, 5-bromopicolinaldehyde and5-bromothiophene-2-carbaldehyde.

Example 2: General Procedure for the Oxidation ofMethylsulfon-Containing Resins Prepared from Fmoc-N-3-MeS-(S)-Val-OH andN-Fmoc-Hydroxylamine 2-Chlorotrityl Resin

A suspension of N-Fmoc-hydroxylamine 2-chlorotrityl resin (20.0 g, 10mmol) in dichloromethane (200 mL) was shaken for 2 hours and drained.The resin was treated with 20% piperidine in DMF (320 mL) for 30minutes, washed with DMF (5×200 mL) and drained completely. In aseparate flask, a solution of(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methyl-3-(methylthio)butanoicacid (7.71 g, 20 mmol), HATU (72 g, 19 mmol) and DIEA (10.5 mL, 60 mmol)in DMF (40 mL) was stirred for three minutes and then added to the resinand mixing under an atmosphere of nitrogen was continued for 2 hours.The resin was drained, washed with DMF (3×200 mL) and drained again. Theresin was then treated with 3-chlorobenzoperoxoic acid (6.9 g, 40 mmol)in DCM (200 mL) for 3 hours. The resin was washed with DMF (3×200 mL),drained and was then treated with 20% piperidine v/v in DMF (320 mL) for30 minutes. After draining again and washing with DMF (5×200 mL), theresin was drained completely and 4-ethynylbenzoic acid (4.38 g, 30mmol), HATU (10.5 g, 28.5 mmol) and DIEA (10.5 ml, 60 mmol) dissolved inDMF (40 mL) were added to the resin. Mixing under an atmosphere ofnitrogen was continued for 2 hours after which the resin was drained,washed with DMF (5×200 mL) and drained again. A solution of therespective halo-aryl- or halo-heteroarylaldehyde (40 mmol) and DIEA(17.5 ml, 100 mmol) in DMF (400 mL) was purged with a stream of nitrogenfor two minutes and then added to the resin. After mixing for 5 minutes,PdCl₂(PPh₃)₂ (1.40 g, 2.0 mmol) and CuI (950 mg, 5.0 mmol) were addedand the mixture was mixing was continued under an atmosphere of nitrogenfor 48 hours. The resin was drained, washed with DMF (4×200 mL) and MeOH(3×200 mL) and dried in vacuo.

Using this procedure, all aldehyde resins were obtained using4-iodobenzaldehyde, 5-bromopicolinaldehyde and5-bromothiophene-2-carbaldehyde.

Example 3: General Procedure for the Reductive Amination of theAldehyde-Containing Resins with Primary and Secondary Amines

A solution of the amine (1.5 mmol) and trimethyl orthoformate (180 μL,1.625 mmol) in THE (20 mL) was added to the aldehyde-containing resin(105 mg, 0.25 mmol). An atmosphere of nitrogen was established and aftermixing for 5 minutes, acetic acid (180 μL, 3.08 mmol) followed by asolution of NaBH₃CN (71 mg, 1.125 mmol) in methanol (1 mL) was added.Mixing was continued for 44 hours after which the resin was filtered,drained and washed with DMF (2×10 mL) and methanol (3×10 mL), drainedagain and dried in vacuo. Cleavage from the resin was achieved bytreatment with trifluoroacetic acid (10 mL) for 30 minutes. The solutionwas collected and concentrated to dryness to give a crude residue whichwas purified by preparative HPLC using a e.g. Gilson GX-281semi-preparative HPLC system equipped with a Luna 200×25 mm (C18, 10μ)or a Gemini 150×30 mm (C18, 5μ) column applying a gradient consisting of0.1% TFA/water and acetonitrile.

The product containing fractions were collected, concentrated byfreeze-drying and the residual trifluoroacetic acid was removed byanother reverse-phase chromatography using a gradient consisting ofaqueous ammonium hydrogencarbonate (7.5 mmol/L) and acetonitrile.

Using this procedure, the following compounds can be synthesized:Compound No.: 1-216, 219-275, 289-374, 378-415.

Example 4: Synthesis of(2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butanoicAcid

Step 1:(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxy-3-methylbutanoicAcid

To a solution of (S)-2-amino-3-hydroxy-3-methylbutanoic acidhydrochloride (30.1 g, 177 mmol) in a mixture of dioxane (500 mL) andwater (250 mL) was added an aqueous NaHCO₃ solution (44.7 g in 500 mLwater) at 20° C. The reaction mixture was stirred at this temperaturefor 30 minutes. Then a solution of (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidin-1-yl) carbonate (59.9 g, 177 mmol) in dioxane (625mL) was added. The resulting mixture was then stirred at roomtemperature for 3 hours. The dioxane was removed in vacuo and theremaining solution washed with methyl-tert-butylether (3×1000 mL). Theaqueous phase was then acidified with 1.0 M hydrochloric acid until thepH 2-3 was reached and was then extracted with ethyl acetate (4×800 mL).The organic phases were combined, washed with brine, dried, filtered andconcentrated to give the title compound.

Step 2:(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butanoicAcid

N,N-Diisopropylethylamine (36.4 g, 281 mmol) was added to a solution of(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxy-3-methylbutanoicacid (20 g, 56.3 mmol) in dichloromethane (500 mL) at 0° C. over aperiod of 20 minutes. Then, tert-butyldimethylsilyltrifluoromethanesulfonate (59.5 g, 225 mmol) was added dropwise to themixture and after stirring for 4 hours at 0° C. All volatiles wereremoved in vacuo and to the residue ethyl acetate (400 mL) was added.1.0 M hydrochloric acid was added until pH 2-3 was reached and theaqueous layer was extracted with ethyl acetate (4×300 mL). The combinedorganic phases were washed with brine, dried, filtered and concentratedto give the crude product which was purified by column chromatography onsilica gel (petroleum ether/ethyl acetate) to provide the title compoundas a solid. ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J=7.6 Hz, 2H), 7.61 (dd,J=6.8 Hz, J=6.4 Hz, 2H), 7.30-7.41 (m, 4H), 5.56 (d, J=9.2 Hz, 1H), 4.2(d, J=6.8 Hz, 2H), 4.23-4.30 (m, 2H), 1.45 (s, 3H), 1.30 (s, 3H), 0.92(s, 9H), 0.19 (s, 3H), 0.18 (s, 3H).

Example 5: Synthesis of(2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-3-methylsulfanyl-butanoicAcid

To a solution of (R)-2-amino-3-mercapto-3-methylbutanoic acid inmethanol was added sodium (3.08 g, 134 mmol) followed by iodomethane (5g, 35.2 mmol). The reaction mixture was stirred for 3 hours at 25° C.and then concentrated in vacuo. The residue was treated with 1 Mhydrochloric acid until pH 7 was reached and the mixture was thendiluted with water (50 mL). NaHCO₃ (5.6 g, 67 mmol) and a solution of(9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate in acetonewas added After stirring at 25° C. for 3 hours, the solution wasconcentrated in vacuo and treated with 1 M hydrochloric acid until pH 4was reached. The mixture was then extracted with ethyl acetate (4×50 mL)and the combined organic layers were evaporated to dryness and theresidue submitted to column chromatography on silica gel (ethylacetate/petroleum ether 1:100 to 1:10) to provide the title compound asa solid. MS: 385.8 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J=7.6 Hz,2H), 7.61 (d, J=7.2 Hz, 2H), 7.32-7.43 (m, 4H), 5.57 (d, J=7.6 Hz, 1H),4.3-4.5 (m, 3H), 4.25 (t, J=6.8 Hz, 1H), 2.10 (s, 3H), 1.43 (s, 3H),1.39 (s, 3H).

Example 6: Synthesis of(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-(2-methyl-1,3-dioxolan-2-yl)acetic Acid

Step 1: Synthesis of benzyl(2S)-2-(benzyloxycarbonylamino)-3-oxo-butanoate

To a mixture of (benzyl(2S,3R)-2-(benzyloxycarbonylamino)-3-hydroxy-butanoate (20 g, 58.2 mmol)in dichloromethane (300 mL) was added Dess-Martin Periodinane (37.1 g,87 mmol) and NaHCO₃ (0.489 g, 5.82 mmol) at 0° C. The mixture was thenstirred at room temperature for 16 hours and concentrated under reducedpressure to remove all volatiles. To the mixture was then addedsaturated Na₂SO₃ (400 mL) and ethyl acetate (400 mL) and both layersshaken vigorously. The aqueous phase was separated and extracted withethyl acetate (1×400 mL). The combined organic layers were washed withbrine (3×400 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to provide the crude title compound which was used inthe next step without further purification.

Step 2: Synthesis of benzyl(2S)-2-(benzyloxycarbonylamino)-2-(2-methyl-1,3-dioxolan-2-yl) acetate

A solution of benzyl (2S)-2-(benzyloxycarbonylamino)-3-oxo-butanoate (40g, 117 mmol), 4-methylbenzenesulfonic acid hydrate (22.29 g, 117 mmol)in ethane-1,2-diol (400 mL) and tetrahydrofuran (50 mL) was stirred atambient temperature for 16 hours. The reaction mixture was thenconcentrated under reduced pressure and the residue was purified byreverse phase preparative HPLC applying a water/acetonitrile gradientwithout additives to provide the title compound.

Step 3: (2S)-2-amino-2-(2-methyl-1,3-dioxolan-2-yl) acetic Acid

A mixture of benzyl(2S)-2-(benzyloxycarbonylamino)-2-(2-methyl-1,3-dioxolan-2-yl) acetate(8 g, 20.76 mmol) and Pd(OH)₂ on carbon (1 g, 20% purity) in methanol(200 mL) was stirred at ambient temperature under an atmosphere ofhydrogen (50 psi) for 16 hours. The mixture was filtered andconcentrated under reduced pressure to provide the crude title compoundwhich was used in the next step without further purification.

Step 4:(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-(2-methyl-1,3-dioxolan-2-yl)acetic Acid

To a mixture of (S)-2-amino-2-(2-methyl-1,3-dioxolan-2-yl) acetic acid(4 g, 24.82 mmol) and NaHCO₃ (6.26 g, 74.5 mmol) in acetone (50 mL) andwater (50 mL) was added a solution of (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidin-1-yl) carbonate (9.21 g, 27.3 mmol) in acetone (20mL) under stirring at ambient temperature and stirring was continued for2 hours. All volatiles were then removed under reduced pressure and theresidue was combined with water (20 mL). The resulting mixture waswashed with ethyl acetate (50 mL), the aqueous layer was acidified with3 M HCl to pH=4. The precipitate was collected by filtration and washedwith water (30 mL) and dried under freeze-drying condition to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 7.89 (d, J=7.6 Hz, 2H),7.78 (d, J=7.6 Hz, 2H), 7.69 (m, 2H), 7.42 (dd, J=7.6 Hz, 2H), 7.33 (dd,J=7.6 Hz, 2H) 4.1-4.4 (m, 4H), 3.7-4.0 (m, 4H), 1.38 (s, 3H).

Example 7: Synthesis of(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxyimino-butanoicAcid

Step 1: Synthesis of benzyl(2S)-2-(benzyloxycarbonylamino)-3-oxo-butanoate

To a mixture of (benzyl(2S,3R)-2-(benzyloxycarbonylamino)-3-hydroxy-butanoate (20 g, 58.2 mmol)in dichloromethane (300 mL) was added Dess-Martin Periodinane (37.1 g,87 mmol) and NaHCO₃ (0.489 g, 5.82 mmol) at 0° C. The mixture was thenstirred at room temperature for 16 hours and concentrated under reducedpressure to remove all volatiles. To the mixture was then addedsaturated Na₂SO₃ (400 mL) and ethyl acetate (400 mL) and both layersshaken vigorously. The aqueous phase was separated and extracted withethyl acetate (1×400 mL). The combined organic layers were washed withbrine (3×400 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to provide the crude title compound which was used inthe next step without further purification.

Step 2: Synthesis of benzyl(2S)-2-(benzyloxycarbonylamino)-3-methoxyimino-butanoate

Benzyl (2S)-2-(benzyloxycarbonylamino)-3-oxo-butanoate (0.5 g, 1.46mmol) was added to a solution of methoxylamine hydrochloride (183 mg,2.197 mmol) and titanium (IV) isopropoxide (83 mg, 0.29 mmol) in DIEA(0.767 mL) and tetrahydrofuran (10 mL) at 20° C. The reaction mixturewas heated at 72° C. for 12 hours and then diluted with water (10 mL).The aqueous layer was extracted with dichloromethane and the combinedorganic extracts were washed with 10% aqueous HCl (50 mL), saturatedNaHCO₃ (50 mL) and brine (50 mL) and then dried over Na₂SO₄. It was thenfiltered and concentrated under reduced pressure to give a residue whichwas purified by column chromatography on silica gel (petroleumether/ethyl acetate) to provide the title compound.

Step 3: (2S)-2-Amino-3-methoxyimino-butanoic Acid

To a solution of benzyl(2S)-2-(benzyloxycarbonylamino)-3-methoxyimino-butanoate (50 g, 135mmol) in methanol (1000 mL) was added palladium on carbon (15%, 10 g)and an atmosphere of nitrogen (15 psi) was established. The reactionmixture was then stirred at 20° C. for 90 minutes and all solids removedby filtration. The solution was collected and concentrated to providethe title compound.

Step 4: Synthesis of(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxyimino-butanoicAcid

(9H-Fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (69.2 g,205 mmol) was added to a solution of(S)-2-amino-3-(methoxyimino)-butanoic acid (20 g, 137 mmol) in a mixtureif acetone (400 mL) and saturated aqueous NaHCO₃ (400 mL). The solutionwas stirred ambient temperature for 10 hours. Water was then added tothe reaction mixture and the formed precipitate collected by filtration.The filter cake was then purified by flash C18 reverse phasechromatography applying a water/acetonitrile gradient to provide thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=7.6 Hz, 2H), 7.68(d, J=7.6 Hz, 2H), 7.42 (dd, J=7.6 Hz, 2H), 7.33 (dd, J=7.6 Hz, 2H), 6.7(b, 1H), 4.1-4.4 (m, 4H), 3.72 (s, 3H), 1.62 (s, 3H).

Example 8: General Procedure for the Synthesis ofCrotonaldehyde-Containing Resin

A suspension of N-Fmoc-hydroxylamine 2-chlorotrityl resin (50.0 g, 25mmol) in dichloromethane (500 mL) was shaken for 2 hours and drained.The resin was then treated with 20% piperidine in DMF (500 mL) for 30minutes, washed with DMF (5×200 mL) and drained completely. In aseparate flask, Fmoc-N-Val-OH (75 mmol), HATU (27 g, 71.3 mmol) and DIEA(26.0 mL, 150 mmol) were dissolved in DMF (100 mL), stirred for threeminutes and then added to the resin. After mixing under an atmosphere ofnitrogen for 2 hours, the mixture was drained, washed with DMF (3×200mL), treated a second time with the DMF solution ofFmoc-N-Thr(^(t)Bu)-OH (30 g, 75 mmol), HATU (27 g, 71.3 mmol) and DIEA(26.0 mL, 150 mmol). The mixture was left shaking for another 2 hours,washed with DMF(5×200 mL) and drained. The resin was then treated with20% piperidine in DMF (500 mL) for 30 minutes, washed with DMF (5×200mL) and drained completely. 4-iodobenzoic acid (19 g, 75 mmol), HATU (27g, 71.3 mmol) and DIEA (26 mL, 150 mmol) dissolved in DMF (100 mL) werethen added to the resin and the mixture was mixed under an atmosphere ofnitrogen for 1 hour. The mixture was drained, washed with DMF (3×200mL), MeOH (3×200 mL) and drained, dried in vacuo.

A solution of (E)-pent-2-en-4-yn-1-ol (8.21 g, 100 mmol) and DIEA (44mL, 250 mmol) in DMF (250 mL) was purged with a stream of nitrogen fortwo minutes and then added to the resin. After mixing for 5 minutes,PdCl₂(PPh₃)₂ (3.51 g, 5.0 mmol) and CuI (2.38 g, 12.5 mmol) were addedand the mixture was shaken under an atmosphere of nitrogen for 48 hours.The resin was drained, washed with DMF (4×150 mL), dichloromethane(4×100 mL) and drained again. The resin was then treated withDess-Martin periodinane (21.2 g, 50 mmol) and Na₂CO₃ (10.6 g, 100 mmol)in dichloromethane for 1 hour, and drained completely. The resin waswashed with DMF (3×150 mL) and MeOH (3×150 mL) and dried in vacuo.

Example 9: General Procedure for the Reductive Amination of theCrotonaldehyde-Containing Resins with Primary and Secondary Amines

A solution of the amine (2.4 mmol) and trimethyl orthoformate (287 μL,2.6 mmol) in THE (20 mL) was added to a vial containing the resin (186mg). After purging the vessel with nitrogen for 5 minutes, it wastreated with acetic acid (282 μL, 4.92 mmol) followed by a solution ofNaBH₃CN (113 mg, 1.8 mmol) in MeOH (1.0 mL) and mixing under anatmosphere of nitrogen was continued for 48 hours. The resin wasdrained, washed with DMF (2×10 mL) and MeOH (3×10 mL) and drained againand dried under reduced pressure. Cleavage from the resin was achievedby treatment with 30% v/v TFA/DCM (20 mL) and for 30 minutes. Thesolution was collected and concentrated to dryness to give a cruderesidue which was purified by preparative HPLC using a Gilson GX-281semi-preparative HPLC system equipped with a Luna 200×25 mm (C18, 10μ,100A) or a Gemini 150×30 mm (C18, 5 um, 110A) column applying a gradientconsisting of 0.1% TFA/water and acetonitrile. The product containingfractions were collected, concentrated by freeze-drying and the residualtrifluoroacetic acid was removed by another reverse-phase chromatographyusing a gradient consisting of aqueous ammonium hydrogencarbonate (7.5mmol/L) and acetonitrile.

Using this procedure, the following compound can be synthesized:Compound No.: 217.

Example 10: Synthesis ofN-[(1S)-2-(hydroxyamino)-1-(hydroxymethyl)-2-oxo-ethyl]-4-[2-(4-nitrophenyl)ethynyl]benzamide[375] and4-[2-(4-aminophenyl)ethynyl]-N-[(1S)-2-(hydroxyamino)-1-(hydroxymethyl)-2-oxo-ethyl]benzamide[376]

Step 1: Synthesis of methyl(2S)-2-[(4-ethynylbenzoyl)amino]-3-hydroxy-propanoate

4-Ethynylbenzoic acid (300 mg, 2.05 mmol) and HBTU (779 mg, 2.0 mmol)were dissolved in DMF (1 mL) and stirred at ambient temperature. After 5minutes, (S)-methyl 2-amino-3-hydroxypropanoate hydrochloride (351 mg,2.26 mmol), tetrahydrofuran (4 mL) and triethylamine (0.658 ml, 4.7mmol) were added and stirring was continued for 1 hour at ambienttemperature. The reaction mixture was diluted with ethyl acetate andwashed twice with NaHCO₃ solution. The organic layer was washed withbrine, dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (silica, pentane/ethylacetate) to provide the title compound.

Step 2: Synthesis of methyl(2S)-3-hydroxy-2-[[4-[2-(4-nitrophenyl)ethynyl]benzoyl]amino]propanoate

Iodo-4-nitrobenzene (528 mg, 2.12 mmol) and triethylamine (0.34 ml, 2.44mmol) were added to a solution of Pd(PPh₃)₂Cl₂ (29.8 mg, 0.042 mmol) andCuI (12.1 mg, 0.064 mmol) in tetrahydrofuran (5 mL) under an atmosphereof nitrogen. To this mixture was then added dropwise a solution of(S)-methyl 2-(4-ethynylbenzamido)-3-hydroxypropanoate (262 mg, 1.06mmol) in tetrahydrofuran (2 mL). The reaction mixture was taken up onsilica gel and purified by column chromatography on silica gel(pentane/ethyl acetate) to provide the title compound.

Step 3: Synthesis ofN-[(1S)-2-(hydroxyamino)-1-(hydroxymethyl)-2-oxo-ethyl]-4-[2-(4-nitrophenyl)ethynyl]benzamide[375]

Sodium (14 mg, 0.61 mmol) was added to dry methanol (1 mL) and themixture was stirred for 20 minutes. Hydroxylamine hydrochloride (40.6mg, 0.58 mmol) was then added and stirring at ambient temperature wascontinued for 45 minutes. Then, a solution of methyl(2S)-3-hydroxy-2-[[4-[2-(4-nitrophenyl)ethynyl]benzoyl]amino]propanoate(50 mg, 0.14 mmol) in methanol/tetrahydrofuran 1:1 (1 mL) was added andthe reaction mixture stirred overnight. All volatiles were then removedunder reduced pressure and the resulting residue was purified by reversephase preparative HPLC using an Atlantis® C18 column applying a gradientconsisting of 0.1% aqueous formic acid and acetonitrile to provide thetitle compound. ¹H NMR (300 MHz, DMSO-d₆): δ 10.71 (b, 1H), 8.86 (b,1H), 8.45 (d, J=7.96 Hz, 1H), 8.30 (m, 2H), 7.99 (d, J=8.4 Hz, 2H), 7.87(m, 2H), 7.74 (d, J=8.4 Hz, 2H), 4.98 (t, J=5.8 Hz, 1H), 4.43 (m, 1H),3.69 (m, 2H).

Step 4: Synthesis of methyl(2S)-2-[[4-[2-(4-aminophenyl)ethynyl]benzoyl]amino]-3-hydroxy-propanoate

Methyl(2S)-3-hydroxy-2-[[4-[2-(4-nitrophenyl)ethynyl]benzoyl]amino]propanoate(100 mg, 0.27 mmol), 2 M hydrochloric acid (0.54 ml, 1.1 mmol) and iron(106 mg, 1.9 mmol) were stirred in ethanol (2.5 mL) at 80° C. for 3.5hours. The reaction mixture was then concentrated under reduced pressureand the resulting residue taken up in water and extracted withdichloromethane (2×). The organic layers were combined, washed withbrine, dried over MgSO₄ and concentrated under reduced pressure toprovide the title compound which was used in the next step withoutfurther purification.

Step 5: Synthesis of4-[2-(4-aminophenyl)ethynyl]-N-[(1S)-2-(hydroxyamino)-1-(hydroxymethyl)-2-oxo-ethyl]benzamide[376]

Sodium (11.6 mg, 0.5 mmol) was added to dry methanol (1 mL) and stirredfor 20 minutes. Hydroxylamine hydrochloride (33.6 mg, 0.48 mmol) wasthen added and stirring at ambient temperature was continued for 45minutes. Then, a solution of methyl(2S)-2-[[4-[2-(4-aminophenyl)ethynyl]benzoyl]amino]-3-hydroxy-propanoate(38 mg, 0.11 mmol) in methanol/tetrahydrofuran 1:1 (1 mL) was added andthe reaction mixture stirred for 2 hours. Then, another methanolicsolution of hydroxylamine prepared from sodium (11.6 mg, 0.5 mmol),hydroxylamine hydrochloride (33.6 mg, 0.48 mmol) and methanol (1 mL) wasadded to the reaction mixture and heated at 40° C. overnight. Thereaction mixture was allowed to attain room temperature and allvolatiles were then removed under reduced pressure and the resultingresidue was purified by reverse phase preparative HPLC using anAtlantis® C18 column applying a gradient consisting of 0.1% ¹H NMR (300MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.85 (s, 1H), 8.34 (d, J=8.0 Hz, 1H),7.90 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H),6.57 (d, J=8.6 Hz, 2H), 5.64 (s, 2H), 4.98 (t, J=5.6 Hz, 1H), 4.42 (q,J=6.2 Hz, 1H), 3.68 (s, 2H).

Example 11: Synthesis of N-[(1S2R)-2-hydroxy-1-(hydroxycarbamoyl)propyl]-4-[2-(4-nitrophenyl)ethynyl]benzamide [377]

Step 1: Synthesis of(2S)-ethyl-2-[(4-ethynylbenzoyl)amino]-3-methyl-butanoate

4-Ethynylbenzoic acid (600 mg, 4.11 mmol) and HBTU (1557 mg, 4.11 mmol)were dissolved in DMF (3 mL) and stirred at ambient temperature for 5minutes. (S)-ethyl 2-amino-3-methylbutanoate hydrochloride (820 mg, 4.52mmol), tetrahydrofuran (7 mL) and triethylamine (1.316 ml, 9.44 mmol)were then added and the resulting reaction mixture was stirred atambient temperature for 1 hour. The mixture was then diluted with ethylacetate and extracted twice with NaHCO₃ solution. The organic layer waswashed with brine and dried over MgSO4 and concentrated. The resultingresidue was purified by column chromatography on silica gel(pentane/ethyl acetate) to provide the title compound.

Step 2: Synthesis of ethyl(2S)-3-methyl-2-[[4-[2-(4-nitrophenyl)ethynyl]benzoyl]amino]butanoate

A solution of triethylamine (0.235 ml, 1.683 mmol) in tetrahydrofuran (5mL) was added to Pd(PPh₃)₂Cl₂ (20.54 mg, 0.029 mmol), CuI (8.36 mg,0.044 mmol), (2S)-ethyl-2-[(4-ethynylbenzoyl)amino]-3-methyl-butanoate(200 mg, 0.732 mmol) and iodo-4-nitrobenzene (364 mg, 1.463 mmol) underargon and the resulting reaction mixture was stirred for 30 minutes. Thereaction mixture was concentrated and the residue was purified by columnchromatography on silica gel (pentane/ethyl acetate) to provide thetitle compound.

Step 3: Synthesis of(2S)-3-methyl-2-[[4-[2-(4-nitrophenyl)ethynyl]benzoyl]amino]butanoicAcid

To a solution of ethyl(2S)-3-methyl-2-[[4-[2-(4-nitrophenyl)ethynyl]benzoyl]amino]butanoate(133 mg, 0.337 mmol) in tetrahydrofuran (4 mL) was added LiOH (48.5 mg,2.023 mmol) and the mixture was stirred at ambient temperature for 1hour. Water (1 drop) was added and the mixture was allowed to stirovernight. The reaction mixture was acidified and extracted with ethylacetate. The organic layer was washed with brine, dried over MgSO₄ andconcentrated under reduced pressure to provide the title compound withwas used in the next step without further purification.

Step 4: Synthesis ofN-[(1S)-1-(hydroxycarbamoyl)-2-methyl-propyl]-4-[2-(4-nitrophenyl)ethynyl]benzamide[377]

(2S)-3-methyl-2-[[4-[2-(4-nitrophenyl)ethynyl]benzoyl]amino]butanoicacid (33 mg, 0.09 mmol) and HATU (37.7 mg, 0.1 mmol) were stirred for 3minutes in a 1:1 mixture of tetrahydrofuran and DMF at ambienttemperature. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (11.6 mg, 0.1mmol) and triethylamine (0.025 ml, 0.18 mmol) were added and the mixturewas left stirring for another hour. All volatiles were then removedunder reduced pressure and the resulting residue was purified by reversephase preparative HPLC using an Atlantis® C18 column applying a gradientconsisting of 0.1% aqueous formic acid and acetonitrile to provide thetitle compound. ¹H NMR (600 MHz, DMSO-d₆) δ 11.25 (s, 1H), 8.51 (d,J=8.6 Hz, 1H), 8.23 (d, J=8.9 Hz, 2H), 7.91 (d, J=8.9 Hz, 2H), 7.80 (d,J=8.9 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 4.08 (td, J=8.0, 17.3 Hz, 1H),2.03 (m, J=5.9 Hz, 1H), 0.86 (m, J=3.5 Hz, 3H).

Example 12: Synthesis of methyl2-[[4-[2-(4-formylphenyl)ethynyl]benzoyl]amino]-3-methyl-3-nitro-butanoate

4-((4-formylphenyl)ethynyl)benzoic acid (1316 mg, 5.26 mmol) was mixedwith tetrahydrofuran (20 mL) and 2 drops of DMF. Oxalyl chloride (0.506mL, 5.8 mmol) was then added dropwise and the reaction mixture stirredat room temperature for 4 hours. More tetrahydrofuran (100 mL) was addedto the slurry and after 1 hour, methyl 2-amino-3-methyl-3-nitrobutanoate(927 mg, 5.26 mmol) was added to the yellow solution. The reactionmixture was allowed to stir at ambient temperature overnight, was thendiluted with ethyl acetate and washed with saturated aqueous sodiumhydrogen carbonate. The organic phase was separated, dried over MgSO₄,filtered and evaporated under reduced pressure to provide the titlecompound which was used in the next steps without further purification.MS: 409.1 (M+1).

Example 13: General Procedure for the Synthesis of Compounds in SolutionPhase Containing a Nitro-Valine as the Amino Acid

To a mixture of methyl2-[[4-[2-(4-formylphenyl)ethynyl]benzoyl]amino]-3-methyl-3-nitro-butanoate(65 mg, 0.16 mmol) in tetrahydrofuran (1 mL) was added the respectiveamine (0.16 mmol) and the solution was stirred for 30 min at roomtemperature. Then, sodium triacetoxyborohydride (135 mg, 0.64 mmol) wasadded and the reaction mixture stirred at room temperature until all ofthe methyl2-[[4-[2-(4-formylphenyl)ethynyl]benzoyl]amino]-3-methyl-3-nitro-butanoatewas consumed. Dichloromethane was then added and the mixture washed with0.1 N HCl. The organic phase was separated, dried over with MgSO₄,filtered and evaporated to dryness under reduced pressure. The resultingresidue was dissolved in a 1:1 mixture of methanol and tetrahydrofuran(1 mL) and hydroxylamine (50% in water, 0.3 mL, 4.9 mmol) and KCN (1.8mg, 0.028 mmol) were added. The resulting reaction mixture was stirreduntil all the starting material was consumed or until the reaction didnot progress any further. The mixture was then purified by preparativereverse-phase HPLC using an XBridge® column and a gradient consisting ofacetonitrile/water+0.1% formic acid or for the more basic compounds agradient consisting of acetonitrile/water+0.1% ammonia to provide thetitle compounds.

Using this procedure, the following compounds can be synthesized:Compound No.: 218, 276-288.

Specific Compounds

Table A provides for each of the exemplified compounds the structureaccording to Formula 1 below.

Compounds of Formula A:

The residue A in Table A is described either in form of a molecularformula or in form of a chemical name, in this latter case A is an aminewhich is inked with its nitrogen atom to residue L.

In the column C_(a) the stereochemistry of the atom C_(a) is denoted. Ifthere is no entry in column C_(a) then both stereoisomers regardingC_(a) are present.

The values for M in Table A have the following meaning:

para phenyl

meta phenyl

thiazole

pyridine

thiophene

furan

ethenyl

The orientation of the residues with regard to Formula 1 is as drawn.

TABLE A No A L M n R1 Ca 1 cyclopropylamine —CH₂— meta phenyl 1 —CH₂OH(S) 2 (CH₃)₂CHNH— —CH₂— meta phenyl 1 —CH₂OH (S) 3 CH₂CHCH₂NH— —CH₂—meta phenyl 1 —CH₂OH (S) 4 (CH₃)₃CCH₂NH— —CH₂— meta phenyl 1 —CH₂OH (S)5 CH₃O(CH₂)₂NH— —CH₂— meta phenyl 1 —CH₂OH (S) 6 (CH₃)₂N(CH₂)₂NH— —CH₂—meta phenyl 1 —CH₂OH (S) 7 CO₂HCH₂NH— —CH₂— meta phenyl 1 —CH₂OH (S) 8(C₂H₅)₂N— —CH₂— meta phenyl 1 —CH₂OH (S) 9 morpholine —CH₂— meta phenyl1 —CH₂OH (S) 10 4-tert-butyl-piperidine —CH₂— meta phenyl 1 —CH₂OH (S)11 4-phenyl-piperidine —CH₂— meta phenyl 1 —CH₂OH (S) 124-phenyl-piperazine —CH₂— meta phenyl 1 —CH₂OH (S) 131-(pyridin-2-yl)-piperazine —CH₂— meta phenyl 1 —CH₂OH (S) 141,2,3,4-tetrahydro-isoquinoline —CH₂— meta phenyl 1 —CH₂OH (S) 15heliamine —CH₂— meta phenyl 1 —CH₂OH (S) 16 benzylamine —CH₂— metaphenyl 1 —CH₂OH (S) 17 N-methylbenzylamine —CH₂— meta phenyl 1 —CH₂OH(S) 18 4-chlorobenzylamine —CH₂— meta phenyl 1 —CH₂OH (S) 194-methoxybenzylamine —CH₂— meta phenyl 1 —CH₂OH (S) 204-dimethylaminobenzylamine —CH₂— meta phenyl 1 —CH₂OH (S) 214-trifluoromethylbenzylamine —CH₂— meta phenyl 1 —CH₂OH (S) 224-pyridylmethanamine —CH₂— meta phenyl 1 —CH₂OH (S) 233,4-dimethylbenzylamine —CH₂— meta phenyl 1 —CH₂OH (S) 24cyclopropylamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 25 (CH₃)₂CHNH— —CH₂—meta phenyl 1 —CH(CH₃)₂ (S) 26 CH₂CHCH₂NH— —CH₂— meta phenyl 1 —CH(CH₃)₂(S) 27 (CH₃)₃CCH₂NH— —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 28 CH₃O(CH₂)₂NH——CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 29 (CH₃)₂N(CH₂)₂NH— —CH₂— meta phenyl1 —CH(CH₃)₂ (S) 30 CO₂HCH₂NH— —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 31(C₂H₅)₂N— —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 32 morpholine —CH₂— metaphenyl 1 —CH(CH₃)₂ (S) 33 1,1-dioxo-thiomorpholine —CH₂— meta phenyl 1—CH(CH₃)₂ (S) 34 4-tert-butyl-piperidine —CH₂— meta phenyl 1 —CH(CH₃)₂(S) 35 4-phenyl-piperidine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 364-phenyl-piperazine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 371-(pyridin-2-y1)-piperazine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 381,2,3,4-tetrahydro-isoquinoline —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 39heliamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 40 benzylamine —CH₂— metaphenyl 1 —CH(CH₃)₂ (S) 41 N-methylbenzylamine —CH₂— meta phenyl 1—CH(CH₃)₂ (S) 42 4-chlorobenzylamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S)43 4-methoxybenzylamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 444-dimethylaminobenzylamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 454-trifluoromethylbenzylamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 464-pyridylmethanamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 473,4-dimethylbenzylamine —CH₂— meta phenyl 1 —CH(CH₃)₂ (S) 48 (CH₃)₂CHNH——CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 49 CH₂CHCH₂NH— —CH₂— meta phenyl1 (S)—CH(CH₃)C₂H₅ (S) 50 (CH₃)₃CCH₂NH— —CH₂— meta phenyl 1(S)—CH(CH₃)C₂H₅ (S) 51 CH₃O(CH₂)₂NH— —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅(S) 52 (CH₃)₂N(CH₂)₂NH— —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 53CO₂HCH₂NH— —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 54 (C₂H₅)₂N— —CH₂—meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 55 morpholine —CH₂— meta phenyl 1(S)—CH(CH₃)C₂H₅ (S) 56 1,1-dioxo-thiomorpholine —CH₂— meta phenyl 1(S)—CH(CH₃)C₂H₅ (S) 57 4-tert-butyl-piperidine —CH₂— meta phenyl 1(S)—CH(CH₃)C₂H₅ (S) 58 4-phenyl-piperidine —CH₂— meta phenyl 1(S)—CH(CH₃)C₂H₅ (S) 59 4-phenyl-piperazine —CH₂— meta phenyl 1(S)—CH(CH₃)C₂H₅ (S) 60 1-(pyridin-2-yl)-piperazine —CH₂— meta phenyl 1(S)—CH(CH₃)C₂H₅ (S) 61 1,2,3,4-tetrahydro-isoquinoline —CH₂— meta phenyl1 (S)—CH(CH₃)C₂H₅ (S) 62 heliamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅(S) 63 benzylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 64N-methylbenzylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 654-chlorobenzylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 664-methoxybenzylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 674-dimethylaminobenzylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 684-trifluoromethylbenzylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 694-pyridylmethanamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 703,4-dimethylbenzylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 71cyclopropylamine —CH₂— para phenyl 1 —CH₂OH (S) 72 (CH₃)₂CHNH— —CH₂—para phenyl 1 —CH₂OH (S) 73 CH₂CHCH₂NH— —CH₂— para phenyl 1 —CH₂OH (S)74 CH₃O(CH₂)₂NH— —CH₂— para phenyl 1 —CH₂OH (S) 75 (CH₃)₂N(CH₂)₂NH——CH₂— para phenyl 1 —CH₂OH (S) 76 (C₂H₅)₂N— —CH₂— para phenyl 1 —CH₂OH(S) 77 morpholine —CH₂— para phenyl 1 —CH₂OH (S) 781,1-dioxo-thiomorpholine —CH₂— para phenyl 1 —CH₂OH (S) 794-tert-butyl-piperidine —CH₂— para phenyl 1 —CH₂OH (S) 804-phenyl-piperidine —CH₂— para phenyl 1 —CH₂OH (S) 814-phenyl-piperazine —CH₂— para phenyl 1 —CH₂OH (S) 821-(pyridin-2-yl)-piperazine —CH₂— para phenyl 1 —CH₂OH (S) 831,2,3,4-tetrahydro-isoquinoline —CH₂— para phenyl 1 —CH₂OH (S) 84heliamine —CH₂— para phenyl 1 —CH₂OH (S) 85 benzylamine —CH₂— paraphenyl 1 —CH₂OH (S) 86 N-methylbenzylamine —CH₂— para phenyl 1 —CH₂OH(S) 87 4-chlorobenzylamine —CH₂— para phenyl 1 —CH₂OH (S) 884-methoxybenzylamine —CH₂— para phenyl 1 —CH₂OH (S) 894-trifluoromethylbenzylamine —CH₂— para phenyl 1 —CH₂OH (S) 904-pyridylmethanamine —CH₂— para phenyl 1 —CH₂OH (S) 913,4-dimethylbenzylamine —CH₂— para phenyl 1 —CH₂OH (S) 92cyclopropylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 93 (CH₃)₂CHNH— —CH₂—para phenyl 1 —CH(CH₃)₂ (S) 94 CH₂CHCH₂NH— —CH₂— para phenyl 1 —CH(CH₃)₂(S) 95 (CH₃)₃CCH₂NH— —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 96 CH₃O(CH₂)₂NH——CH₂— para phenyl 1 —CH(CH₃)₂ (S) 97 (C₂H₅)₂N— —CH₂— para phenyl 1—CH(CH₃)₂ (S) 98 morpholine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 991,1-dioxo-thiomorpholine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1004-phenyl-piperidine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1011-(pyridin-2-yl)-piperazine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1021,2,3,4-tetrahydro-isoquinoline —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 103heliamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 104 benzylamine —CH₂— paraphenyl 1 —CH(CH₃)₂ (S) 105 N-methylbenzylamine —CH₂— para phenyl 1—CH(CH₃)₂ (S) 106 4-chlorobenzylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S)107 4-methoxybenzylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1084-dimethylaminobenzylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1094-trifluoromethylbenzylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1104-pyridylmethanamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1113,4-dimethylbenzylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 112cyclopropylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 113 CH₂CHCH₂NH——CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 114 (CH₃)₃CCH₂NH— —CH₂— paraphenyl 1 (S)—CH(CH₃)C₂H₅ (S) 115 CH₃O(CH₂)₂NH— —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 116 (CH₃)₂N(CH₂)₂NH— —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 117 CO₂HCH₂NH— —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅(S) 118 (C₂H₅)₂N— —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 119 morpholine—CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 120 4-tert-butyl-piperidine—CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 121 4-phenyl-piperidine —CH₂—para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 122 4-phenyl-piperazine —CH₂— paraphenyl 1 (S)—CH(CH₃)C₂H₅ (S) 123 1-(pyridin-2-yl)-piperazine —CH₂— paraphenyl 1 (S)—CH(CH₃)C₂H₅ (S) 124 1,2,3,4-tetrahydro-isoquinoline —CH₂—para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 125 heliamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 126 benzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅(S) 127 N-methylbenzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 1284-chlorobenzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 1294-methoxybenzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 1304-dimethylaminobenzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 1314-trifluoromethylbenzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 1324-pyridylmethanamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 1333,4-dimethylbenzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 1344-dimethylaminobenzylamine —CH₂— para phenyl 1 —CH₂OH (S) 1354-phenyl-piperazine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 136 (CH₃)₃CCH₂NH——CH₂— para phenyl 1 —CH₂OH (S) 137 CO₂HCH₂NH— —CH₂— para phenyl 1 —CH₂OH(S) 138 (CH₃)₂N(CH₂)₂NH— —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 139CO₂HCH₂NH— —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 140 4-tert-butyl-piperidine—CH₂— para phenyl 1 —CH(CH₃)₂ (S) 141 (CH₃)₂CHNH— —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 142 1,1-dioxo-thiomorpholine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 143 1,1-dioxo-thiomorpholine —CH₂— meta phenyl 1—CH₂OH (S) 144 cyclopropylamine —CH₂— meta phenyl 1 (S)—CH(CH₃)C₂H₅ (S)145 pyrrolidine —CH₂— para phenyl 1 —CH₂OH (S) 146 N-methylpiperazine—CH₂— para phenyl 1 —CH₂OH (S) 147 cyclobutylamine —CH₂— para phenyl 1—CH₂OH (S) 148 cyclopentylamine —CH₂— para phenyl 1 —CH₂OH (S) 149cyclohexylamine —CH₂— para phenyl 1 —CH₂OH (S) 150 CH₃NH— —CH₂— paraphenyl 1 —CH₂OH (S) 151 C₂H₅NH— —CH₂— para phenyl 1 —CH₂OH (S) 152CH₃(CH₂)₂NH— —CH₂— para phenyl 1 —CH₂OH (S) 153 CH₃O(CH₂)₃NH— —CH₂— paraphenyl 1 —CH₂OH (S) 154 CH₃O(CH₂)₂N(CH₃)— —CH₂— para phenyl 1 —CH₂OH (S)155 2,6-dimethylmorpholine —CH₂— para phenyl 1 —CH₂OH (S) 156 piperidine—CH₂— para phenyl 1 —CH₂OH (S) 157 3-pyridylmethanamine —CH₂— paraphenyl 1 —CH₂OH (S) 158 2-pyridylmethanamine —CH₂— para phenyl 1 —CH₂OH(S) 159 furfurylamine —CH₂— para phenyl 1 —CH₂OH (S) 1602-thienylmethanamine —CH₂— para phenyl 1 —CH₂OH (S) 1614-methylbenzylamine —CH₂— para phenyl 1 —CH₂OH (S) 162tetrahydrofurfurylamine —CH₂— para phenyl 1 —CH₂OH (S) 163imidazol-2-ylmethanamine —CH₂— para phenyl 1 —CH₂OH (S) 164CH₃OCH₂CH(CH₃)NH— —CH₂— para phenyl 1 —CH₂OH (S) 1652,6-dimethylmorpholine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 166 piperidine—CH₂— para phenyl 1 —CH(CH₃)₂ (S) 167 3-pyridylmethanamine —CH₂— paraphenyl 1 —CH(CH₃)₂ (S) 168 (2-chloro-4- —CH₂— para phenyl 1 —CH(CH₃)₂(S) pyridyl)methanamine 169 2-pyridylmethanamine —CH₂— para phenyl 1—CH(CH₃)₂ (S) 170 furfurylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1712-thienylmethanamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 1724-methylbenzylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 173imidazol-2-ylmethanamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 174pyrrolidine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 175N-methylpiperazine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 176 C₂H₅NH——CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 177 CH₃O(CH₂)₃NH— —CH₂— paraphenyl 1 (S)—CH(CH₃)C₂H₅ (S) 178 CH₃O(CH₂)₂N(CH₃)— —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 179 3-pyridylmethanamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 180 2-pyridylmethanamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 181 furfurylamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 182 2-thienylmethanamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 183 tetrahydrofurfurylamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 184 imidazol-2-ylmethanamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 185 CH₃OCH₂CH(CH₃)NH— —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 186 1,4-oxazepane —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 187 piperidine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅(S) 188 thiazol-2-ylmethanamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S)189 4-methylbenzylamine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 190(2-chloro-4- —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) pyridyl)methanamine191 2,6-dimethylmorpholine —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 192NCCH₂NH— —CH₂— para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 193 CH₃(CH₂)₂NH— —CH₂—para phenyl 1 (S)—CH(CH₃)C₂H₅ (S) 194 CH₃NH— —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 195 cyclohexylamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 196 cyclopentylamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 197 cyclobutylamine —CH₂— para phenyl 1(S)—CH(CH₃)C₂H₅ (S) 198 CH₃OCH₂CH(CH₃)NH— —CH₂— para phenyl 1 —CH(CH₃)₂(S) 199 thiazol-2-ylmethanamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 200tetrahydrofurfurylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 201 C₂H₅NH——CH₂— para phenyl 1 —CH(CH₃)₂ (S) 202 1,4-oxazepane —CH₂— para phenyl 1—CH(CH₃)₂ (S) 203 CH₃O(CH₂)₂N(CH₃)— —CH₂— para phenyl 1 —CH(CH₃)₂ (S)204 NCCH₂NH— —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 205 CH₃O(CH₂)₃NH— —CH₂—para phenyl 1 —CH(CH₃)₂ (S) 206 CH₃(CH₂)₂NH— —CH₂— para phenyl 1—CH(CH₃)₂ (S) 207 CH₃NH— —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 208cyclohexylamine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 209 cyclopentylamine—CH₂— para phenyl 1 —CH(CH₃)₂ (S) 210 cyclobutylamine —CH₂— para phenyl1 —CH(CH₃)₂ (S) 211 N-methylpiperazine —CH₂— para phenyl 1 —CH(CH₃)₂ (S)212 pyrrolidine —CH₂— para phenyl 1 —CH(CH₃)₂ (S) 213thiazol-2-ylmethanamine —CH₂— para phenyl 1 —CH₂OH (S) 214 (2-chloro-4-—CH₂— para phenyl 1 —CH₂OH (S) pyridyl)methanamine 215 1,4-oxazepane—CH₂— para phenyl 1 —CH₂OH (S) 216 NCCH₂NH— —CH₂— para phenyl 1 —CH₂OH(S) 217 morpholine —CH₂— ethenyl 1 —CH(CH₃)₂ (S) 218 cyclopropylamine—CH₂— para phenyl 1 —C(CH₃)₂NO₂ 219 cyclopropylamine —CH₂— para phenyl 1—C(CH₃)₂OH (S) 220 CH₂CHCH₂NH— —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 221CH₃O(CH₂)₂NH— —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 222 morpholine —CH₂—para phenyl 1 —C(CH₃)₂OH (S) 223 benzylamine —CH₂— para phenyl 1—C(CH₃)₂OH (S) 224 4-methoxybenzylamine —CH₂— para phenyl 1 —C(CH₃)₂OH(S) 225 pyrrolidine —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 226cyclobutylamine —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 227 cyclopentylamine—CH₂— para phenyl 1 —C(CH₃)₂OH (S) 228 3-pyridylmethanamine —CH₂— paraphenyl 1 —C(CH₃)₂OH (S) 229 (2-chloro-4- —CH₂— para phenyl 1 —C(CH₃)₂OH(S) pyridyl)methanamine 230 2-pyridylmethanamine —CH₂— para phenyl 1—C(CH₃)₂OH (S) 231 furfurylamine —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 2322-thienylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 2334-methylbenzylamine —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 234tetrahydrofurfurylamine —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 235cyclopropylamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 236 CH₂CHCH₂NH——CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 237 CH₃O(CH₂)₂NH— —CH₂— para phenyl1 —C(CH₃)₂SCH₃ (R) 238 morpholine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R)239 benzylamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 2404-methoxybenzylamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 2414-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 242pyrrolidine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 243 cyclobutylamine—CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 244 cyclopentylamine —CH₂— paraphenyl 1 —C(CH₃)₂SCH₃ (R) 245 CH₃(CH₂)₂NH— —CH₂— para phenyl 1—C(CH₃)₂SCH₃ (R) 246 NCCH₂NH— —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 2473-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 248(2-chloro-4- —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) pyridyl)methanamine249 2-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 250furfurylamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 2512-thienylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 2524-methylbenzylamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 253tetrahydrofurfurylamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 254thiazol-2-ylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SCH₃ (R) 255cyclopropylamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 256 CH₂CHCH₂NH——CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 257 CH₃O(CH₂)₂NH— —CH₂— paraphenyl 1 —C(CH₃)₂SO₂CH₃ (R) 258 morpholine —CH₂— para phenyl 1—C(CH₃)₂SO₂CH₃ (R) 259 benzylamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃(R) 260 4-methoxybenzylamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 2614-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 262pyrrolidine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 263 cyclobutylamine—CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 264 cyclopentylamine —CH₂— paraphenyl 1 —C(CH₃)₂SO₂CH₃ (R) 265 CH₃(CH₂)₂NH— —CH₂— para phenyl 1—C(CH₃)₂SO₂CH₃ (R) 266 NCCH₂NH— —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R)267 3-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 268(2-chloro-4- —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) pyridyl)methanamine269 2-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 270furfurylamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 2712-thienylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 2724-methylbenzylamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 273tetrahydrofurfurylamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 274thiazol-2-ylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂SO₂CH₃ (R) 2754-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂OH (S) 276 benzylamine—CH₂— para phenyl 1 —C(CH₃)₂NO₂ 277 4-chlorobenzylamine —CH₂— paraphenyl 1 —C(CH₃)₂NO₂ 278 4-pyridylmethanamine —CH₂— para phenyl 1—C(CH₃)₂NO₂ 279 4-trifluoromethylbenzylamine —CH₂— para phenyl 1—C(CH₃)₂NO₂ 280 CH₂CHCH₂NH— —CH₂— para phenyl 1 —C(CH₃)₂NO₂ 281(CH₃)₂CHNH— —CH₂— para phenyl 1 —C(CH₃)₂NO₂ 282 2-pyridylmethanamine—CH₂— para phenyl 1 —C(CH₃)₂NO₂ 283 4-methylbenzylamine —CH₂— paraphenyl 1 —C(CH₃)₂NO₂ 284 4-fluorobenzylamine —CH₂— para phenyl 1—C(CH₃)₂NO₂ 285 CH₃O(CH₂)₃NH— —CH₂— para phenyl 1 —C(CH₃)₂NO₂ 2863-pyridylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂NO₂ 287 furfurylamine—CH₂— para phenyl 1 —C(CH₃)₂NO₂ 288 CF₃CH₂NH— —CH₂— para phenyl 1—C(CH₃)₂NO₂ 289 2-thienylmethanamine —CH₂— para phenyl 1 —C(CH₃)₂NO₂ 290cyclopropylamine —CH₂— thiophene 1 —C(CH₃)₂OH (S) 291 CH₂CHCH₂NH— —CH₂—thiophene 1 —C(CH₃)₂OH (S) 292 CH₃O(CH₂)₂NH— —CH₂— thiophene 1—C(CH₃)₂OH (S) 293 morpholine —CH₂— thiophene 1 —C(CH₃)₂OH (S) 294benzylamine —CH₂— thiophene 1 —C(CH₃)₂OH (S) 295 4-methoxybenzylamine—CH₂— thiophene 1 —C(CH₃)₂OH (S) 296 3-pyridylmethanamine —CH₂—thiophene 1 —C(CH₃)₂OH (S) 297 2-pyridylmethanamine —CH₂— thiophene 1—C(CH₃)₂OH (S) 298 furfurylamine —CH₂— thiophene 1 —C(CH₃)₂OH (S) 299(5-methyloxazol-2- —CH₂— thiophene 1 —C(CH₃)₂OH (S) yl)methanamine 300cyclopropylamine —CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R) 301 CH₂CHCH₂NH——CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R) 302 CH₃O(CH₂)₂NH— —CH₂— thiophene 1—C(CH₃)₂SCH₃ (R) 303 morpholine —CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R) 304benzylamine —CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R) 305 4-methoxybenzylamine—CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R) 306 3-pyridylmethanamine —CH₂—thiophene 1 —C(CH₃)₂SCH₃ (R) 307 2-pyridylmethanamine —CH₂— thiophene 1—C(CH₃)₂SCH₃ (R) 308 furfurylamine —CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R)309 CF₃CH₂NH— —CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R) 310 (5-methyloxazol-2-—CH₂— thiophene 1 —C(CH₃)₂SCH₃ (R) yl)methanamine 311 cyclopropylamine—CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 312 CH₂CHCH₂NH— —CH₂— thiophene 1—C(CH₃)₂SO₂CH₃ (R) 313 CH₃O(CH₂)₂NH— —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃(R) 314 morpholine —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 315 benzylamine—CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 316 4-methoxybenzylamine —CH₂—thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 317 4-pyridylmethanamine —CH₂— thiophene1 —C(CH₃)₂SO₂CH₃ (R) 318 NCCH₂NH— —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R)319 3-pyridylmethanamine —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 3202-pyridylmethanamine —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 321furfurylamine —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 3222-pyrimidinylmethanamine —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 323(5-methyloxazol-2- —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) yl)methanamine324 cyclopropylamine —CH₂— pyridine 1 —C(CH₃)₂OH (S) 325 CH₃O(CH₂)₂NH——CH₂— pyridine 1 —C(CH₃)₂OH (S) 326 morpholine —CH₂— pyridine 1—C(CH₃)₂OH (S) 327 benzylamine —CH₂— pyridine 1 —C(CH₃)₂OH (S) 3284-methoxybenzylamine —CH₂— pyridine 1 —C(CH₃)₂OH (S) 3294-pyridylmethanamine —CH₂— pyridine 1 —C(CH₃)₂OH (S) 3303-pyridylmethanamine —CH₂— pyridine 1 —C(CH₃)₂OH (S) 3312-pyridylmethanamine —CH₂— pyridine 1 —C(CH₃)₂OH (S) 332 furfurylamine—CH₂— pyridine 1 —C(CH₃)₂OH (S) 333 CF₃CH₂NH— —CH₂— pyridine 1—C(CH₃)₂OH (S) 334 (5-methyloxazol-2- —CH₂— pyridine 1 —C(CH₃)₂OH (S)yl)methanamine 335 cyclopropylamine —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R)336 CH₂CHCH₂NH— —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 337 CH₃O(CH₂)₂NH——CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 338 morpholine —CH₂— pyridine 1—C(CH₃)₂SCH₃ (R) 339 benzylamine —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 3404-methoxybenzylamine —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 3414-pyridylmethanamine —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 342 NCCH₂NH——CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 343 2-pyridylmethanamine —CH₂—pyridine 1 —C(CH₃)₂SCH₃ (R) 344 furfurylamine —CH₂— pyridine 1—C(CH₃)₂SCH₃ (R) 345 CF₃CH₂NH— —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 3462-pyrimidinylmethanamine —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) 347(5-methyloxazol-2- —CH₂— pyridine 1 —C(CH₃)₂SCH₃ (R) yl)methanamine 348cyclopropylamine —CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 349 CH₃O(CH₂)₂NH——CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 350 morpholine —CH₂— pyridine 1—C(CH₃)₂SO₂CH₃ (R) 351 benzylamine —CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R)352 4-methoxybenzylamine —CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 3532-pyridylmethanamine —CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 354furfurylamine —CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 355 CF₃CH₂NH— —CH₂—pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 356 2-pyrimidinylmethanamine —CH₂—pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 357 (5-methyloxazol-2- —CH₂— pyridine 1—C(CH₃)₂SO₂CH₃ (R) yl)methanamine 358 NCCH₂NH— —CH₂— thiophene 1—C(CH₃)₂OH (S) 359 thiazol-2-ylmethanamine —CH₂— thiophene 1 —C(CH₃)₂OH(S) 360 2-pyrimidinylmethanamine —CH₂— thiophene 1 —C(CH₃)₂OH (S) 361CH₂CHCH₂NH— —CH₂— pyridine 1 —C(CH₃)₂OH (S) 362 thiazol-2-ylmethanamine—CH₂— pyridine 1 —C(CH₃)₂OH (S) 363 2-pyrimidinylmethanamine —CH₂—pyridine 1 —C(CH₃)₂OH (S) 364 4-pyridylmethanamine —CH₂— thiophene 1—C(CH₃)₂SOH₃ (R) 365 thiazol-2-ylmethanamine —CH₂— thiophene 1—C(CH₃)₂SOH₃ (R) 366 2-pyrimidinylmethanamine —CH₂— thiophene 1—C(CH₃)₂SOH₃ (R) 367 3-pyridylmethanamine —CH₂— pyridine 1 —C(CH₃)₂SOH₃(R) 368 thiazol-2-ylmethanamine —CH₂— pyridine 1 —C(CH₃)₂SOH₃ (R) 369thiazol-2-ylmethanamine —CH₂— thiophene 1 —C(CH₃)₂SO₂CH₃ (R) 370CH₂CHCH₂NH— —CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 371 4-pyridylmethanamine—CH₂— pyridine 1 —C(CH₃)₂SO₂CH₃ (R) 372 NCCH₂NH— —CH₂— pyridine 1—C(CH₃)₂SO₂CH₃ (R) 373 3-pyridylmethanamine —CH₂— pyridine 1—C(CH₃)₂SO₂CH₃ (R) 374 thiazol-2-ylmethanamine —CH₂— pyridine 1—C(CH₃)₂SO₂CH₃ (R) 375 NO₂ — para phenyl 1 —CH₂OH (S) 376 NH₂ — paraphenyl 1 —CH₂OH (S) 377 NO₂ — para phenyl 1 —CH(CH₃)₂ (S) 378cyclopropylamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 379 CH₂CHCH₂NH— —CH₂—para phenyl 1 C═N—OCH₃ (S) 380 CH₃O(CH₂)₂NH— —CH₂— para phenyl 1C═N—OCH₃ (S) 381 morpholine —CH₂— para phenyl 1 C═N—OCH₃ (S) 382benzylamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 383 4-methoxybenzylamine—CH₂— para phenyl 1 C═N—OCH₃ (S) 384 pyrrolidine —CH₂— para phenyl 1C═N—OCH₃ (S) 385 cyclobutylamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 386cyclopentylamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 387 CH₃(CH₂)₂NH— —CH₂—para phenyl 1 C═N—OCH₃ (S) 388 3-pyridylmethanamine —CH₂— para phenyl 1C═N—OCH₃ (S) 389 (2-chloro-4- —CH₂— para phenyl 1 C═N—OCH₃ (S)pyridyl)methanamine 390 2-pyridylmethanamine —CH₂— para phenyl 1C═N—OCH₃ (S) 391 furfurylamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 3922-thienylmethanamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 3934-methylbenzylamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 394tetrahydrofurfurylamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 395thiazol-2-ylmethanamine —CH₂— para phenyl 1 C═N—OCH₃ (S) 396cyclopropylamine —CH₂— para phenyl 1 —COCH₃ (S) 397 CH₂CHCH₂NH— —CH₂—para phenyl 1 —COCH₃ (S) 398 CH₃O(CH₂)₂NH— —CH₂— para phenyl 1 —COCH₃(S) 399 morpholine —CH₂— para phenyl 1 —COCH₃ (S) 400 benzylamine —CH₂—para phenyl 1 —COCH₃ (S) 401 4-methoxybenzylamine —CH₂— para phenyl 1—COCH₃ (S) 402 4-pyridylmethanamine —CH₂— para phenyl 1 —COCH₃ (S) 403pyrrolidine —CH₂— para phenyl 1 —COCH₃ (S) 404 cyclobutylamine —CH₂—para phenyl 1 —COCH₃ (S) 405 cyclopentylamine —CH₂— para phenyl 1 —COCH₃(S) 406 CH₃(CH₂)₂NH— —CH₂— para phenyl 1 —COCH₃ (S) 4073-pyridylmethanamine —CH₂— para phenyl 1 —COCH₃ (S) 408 (2-chloro-4-—CH₂— para phenyl 1 —COCH₃ (S) pyridyl)methanamine 4092-pyridylmethanamine —CH₂— para phenyl 1 —COCH₃ (S) 410 furfurylamine—CH₂— para phenyl 1 —COCH₃ (S) 411 2-thienylmethanamine —CH₂— paraphenyl 1 —COCH₃ (S) 412 4-methylbenzylamine —CH₂— para phenyl 1 —COCH₃(S) 413 tetrahydrofurfurylamine —CH₂— para phenyl 1 —COCH₃ (S) 414thiazol-2-ylmethanamine —CH₂— para phenyl 1 —COCH₃ (S) 4154-pyridylmethanamine —CH₂— para phenyl 1 C═N—OCH₃ (S)

Example 8: Analytics—HPLC Methods

Method 1

Chromatographic System:

Column: Chromolith FastGradient RP-18e from Merck, 2*50 mm

Oven: 35° C.

Eluents: Solvent A: water/HCO₂H (0.1%); Solvent B: acetonitrile/HCO₂H(0.1%)

Flow: 1.2 ml/min

Gradient:

Time [min] Solvent A [%] Solvent B [%] 0.0 90 10 2.0 0 100 2.7 0 100

Run time: 3.5 min (equilibration included)

Method 2

Chromatographic System:

Column: Chromolith FastGradient RP-18e from Merck, 2*50 mm

Oven: 30° C.

Eluents: Solvent A: water/HCO₂H (0.1%); Solvent B: acetonitrile/HCO₂H(0.1%)

Flow: 1.2 ml/min

Gradient:

Time [min] Solvent A [%] Solvent B [%] 0.0 98 2 0.2 98 2 2.2 2 98 2.7 298

Run time: 3.5 min (equilibration included)

Method—3

Chromatographic System:

Column: Xbridge BEH C18 Waters, 2.1×50 mm, 2.5μ

Oven: 40° C.

Eluents: Solvent A: water/HCO₂H (0.05%); Solvent B: acetonitrile/HCO₂H(0.05%)

Flow: 0.8 ml/min

Gradient:

Time [min] Solvent A [%] Solvent B [%] 0.0 98 2 1.2 0 100 1.7 0 100 1.898 2

Run time: 2.2 min+0.5 min equilibration time

Method—4

Chromatographic System:

Column: Phenomenex Jupiter Proteo C18 90A, 4.6×50 mm, 4μ

Oven: 30° C.

Eluents: Solvent A: water/TFA (0.1%); Solvent B: acetonitrile/TFA (0.1%)

Flow: 1.0 ml/min

Gradient:

Time [min] Solvent A [%] Solvent B [%] 0.0 98 2 3.0 0 100 4.0 0 100 4.598 2 5 98 2

Run time: 5 min

Table B provides for each of the exemplified compounds of Table A thecalculated molecular weight (MW), the observed mass signal (m/z), theHPLC retention time (Rt) in minutes and the number of the HPLC method asdescribed above (“HPLC methods”).

TABLE B No Rt m/z MW HPLC method 1 2.15 394.1 393.4 4 2 2.17 396.2 395.54 3 2.17 394.1 393.4 4 4 2.37 424.2 423.5 4 5 2.14 412.3 411.5 4 6 1.99425.2 424.5 4 7 2.04 412.0 411.4 4 8 2.18 410.2 409.5 4 9 2.10 424.2423.5 4 10 2.63 478.3 477.6 4 11 2.60 498.2 497.6 4 12 2.53 499.3 498.64 13 2.04 500.3 499.6 4 14 2.42 470.2 469.5 4 15 2.37 530.2 529.6 4 162.39 444.1 443.5 4 17 2.42 458.2 457.5 4 18 2.52 478.2 477.9 4 19 2.43474.1 473.5 4 20 2.12 487.2 486.6 4 21 2.62 512.2 511.5 4 22 1.99 445.2444.5 4 23 2.58 472.2 471.6 4 24 2.41 406.2 405.5 4 25 2.43 408.3 407.54 26 2.43 407.2 405.5 4 27 2.60 436.3 435.6 4 28 2.40 424.3 423.5 4 292.21 437.2 436.6 4 30 2.31 424.2 423.5 4 31 2.44 422.3 421.5 4 32 2.36436.3 435.5 4 33 2.47 484.1 483.6 4 34 2.84 490.4 489.7 4 35 2.81 510.2509.6 4 36 2.72 511.3 510.6 4 37 2.27 512.3 511.6 4 38 2.65 482.2 481.64 39 2.60 542.2 541.6 4 40 2.61 456.3 455.6 4 41 2.65 470.2 469.6 4 422.74 490.1 490.0 4 43 2.66 486.2 485.6 4 44 2.34 499.2 498.6 4 45 2.81524.3 523.6 4 46 2.22 457.2 456.5 4 47 2.79 484.3 483.6 4 48 2.53 422.3421.5 4 49 2.53 420.2 419.5 4 50 2.70 450.3 449.6 4 51 2.50 438.3 437.54 52 2.31 451.2 450.6 4 53 2.42 438.2 437.5 4 54 2.56 436.2 435.6 4 552.48 450.2 449.5 4 56 2.58 498.1 497.6 4 57 2.94 504.4 503.7 4 58 2.88524.4 523.7 4 59 2.83 525.3 524.7 4 60 2.38 526.3 525.6 4 61 2.75 496.3495.6 4 62 2.69 556.2 555.7 4 63 2.71 470.3 469.6 4 64 2.74 484.3 483.64 65 2.82 504.2 504.0 4 66 2.74 500.3 499.6 4 67 2.44 513.2 512.7 4 682.89 538.2 537.6 4 69 2.32 471.2 470.6 4 70 2.88 499.3 497.6 4 71 2.10394.2 393.4 4 72 2.13 396.2 395.5 4 73 2.13 394.1 393.4 4 74 2.08 412.2411.5 4 75 1.93 425.2 424.5 4 76 2.13 410.2 409.5 4 77 2.04 424.2 423.54 78 2.13 472.1 471.5 4 79 2.62 478.2 477.6 4 80 2.57 498.2 497.6 4 812.50 499.7 498.6 4 82 1.98 500.2 499.6 4 83 2.40 470.2 469.5 4 84 2.34530.2 529.6 4 85 2.36 444.1 443.5 4 86 2.39 458.2 457.5 4 87 2.51 478.1477.9 4 88 2.41 474.1 473.5 4 89 2.61 512.2 511.5 4 90 1.93 445.1 444.54 91 2.57 472.3 471.6 4 92 2.37 406.1 405.5 4 93 2.40 408.1 407.5 4 942.40 406.1 405.5 4 95 2.57 436.1 435.6 4 96 2.35 424.1 423.5 4 97 2.41422.1 421.5 4 98 2.32 436.2 435.5 4 99 2.41 484.1 483.6 4 100 2.77 510.2509.6 4 101 2.23 512.2 511.6 4 102 2.61 482.2 481.6 4 103 2.57 542.2541.6 4 104 2.59 456.2 455.6 4 105 2.63 470.2 469.6 4 106 2.72 490.1490.0 4 107 2.63 486.1 485.6 4 108 2.31 499.2 498.6 4 109 2.79 524.3523.6 4 110 2.18 457.1 456.5 4 111 2.80 484.2 483.6 4 112 2.48 420.2419.5 4 113 2.49 420.2 419.5 4 114 2.66 450.3 449.6 4 115 2.46 438.2437.5 4 116 2.27 451.2 450.6 4 117 2.37 438.1 437.5 4 118 2.51 436.3435.6 4 119 2.43 450.3 449.5 4 120 2.91 504.4 503.7 4 121 2.85 524.3523.7 4 122 2.82 525.4 524.7 4 123 2.33 526.3 525.6 4 124 2.71 496.2495.6 4 125 2.66 556.2 555.7 4 126 2.66 470.2 469.6 4 127 2.71 484.3483.6 4 128 2.80 504.1 504.0 4 129 2.71 500.2 499.6 4 130 2.39 513.2512.7 4 131 2.88 538.3 537.6 4 132 2.29 471.2 470.6 4 133 2.87 498.2497.6 4 134 2.08 487.2 486.6 4 135 2.72 511.2 510.6 4 136 2.32 424.2423.5 4 137 1.94 412.1 411.4 4 138 2.20 438.2 436.6 4 139 2.26 424.1423.5 4 140 2.84 490.3 489.7 4 141 2.50 422.2 421.5 4 142 2.57 498.2497.6 4 143 2.21 472.1 471.5 4 144 2.51 420.2 419.5 4 145 2.25 408.0407.5 4 146 2.14 437.1 436.5 4 147 2.33 408.0 407.5 4 148 2.41 422.1421.5 4 149 2.51 436.1 435.5 4 150 2.16 368.1 367.4 4 151 2.21 382.0381.4 4 152 2.30 396.0 395.5 4 153 2.29 426.0 425.5 4 154 2.26 426.1425.5 4 155 2.35 452.1 451.5 4 156 2.31 422.1 421.5 4 157 2.11 445.0444.5 4 158 2.32 445.0 444.5 4 159 2.35 434.0 433.5 4 160 2.43 450.0449.5 4 161 2.61 458.0 457.5 4 162 2.31 438.1 437.5 4 163 2.08 434.1433.5 4 164 2.30 426.1 425.5 4 165 2.60 464.1 463.6 4 166 2.58 434.1433.5 4 167 2.36 457.1 456.5 4 168 2.61 491.1 491.0 4 169 2.58 457.1456.5 4 170 2.61 446.1 445.5 4 171 2.66 462.0 461.6 4 172 2.80 470.1469.6 4 173 2.33 446.0 445.5 4 174 2.63 434.1 433.5 4 175 2.50 463.1462.6 4 176 2.59 408.1 407.5 4 177 2.65 452.1 451.6 4 178 2.64 452.1451.6 4 179 2.47 471.1 470.6 4 180 2.67 471.1 470.6 4 181 2.69 460.1459.5 4 182 2.76 476.0 475.6 4 183 2.66 464.0 463.6 4 184 2.43 460.0459.6 4 185 2.66 452.1 451.6 4 186 2.60 464.1 463.6 4 187 2.68 448.1447.6 4 188 2.49 477.2 476.6 4 189 2.78 484.2 483.6 4 190 2.57 505.2505.0 4 191 2.56 478.2 477.6 4 192 2.46 419.2 418.5 4 193 2.51 422.2421.5 4 194 2.40 394.2 393.5 4 195 2.67 462.2 461.6 4 196 2.60 448.2447.6 4 197 2.53 434.2 433.5 4 198 2.41 438.2 437.5 4 199 2.38 463.1462.6 4 200 2.40 450.2 449.5 4 201 2.32 394.2 393.5 4 202 2.34 450.2449.5 4 203 2.37 438.2 437.5 4 204 2.35 405.2 404.5 4 205 2.40 438.2437.5 4 206 2.42 408.2 407.5 4 207 2.28 380.2 379.5 4 208 2.59 448.2447.6 4 209 2.49 434.2 433.5 4 210 2.41 420.2 419.5 4 211 2.19 449.2448.6 4 212 2.37 420.2 419.5 4 213 2.13 451.1 450.5 4 214 2.22 479.1478.9 4 215 2.06 438.2 437.5 4 216 2.06 393.1 392.4 4 217 1.32 386385.4568 2 218 0.75 451 450.487 3 219 2.15 422.2 421.5 4 220 2.17 422.2421.5 4 221 2.14 440.2 439.5 4 222 2.10 452.2 451.5 4 223 2.40 472.2471.5 4 224 2.44 502.2 501.6 4 225 2.15 436.2 435.5 4 226 2.22 436.2435.5 4 227 2.31 450.2 449.5 4 228 1.99 473.2 472.5 4 229 2.27 507.1507.0 4 230 2.20 473.2 472.5 4 231 2.27 462.1 461.5 4 232 2.34 478.2477.6 4 233 2.51 486.2 485.6 4 234 2.21 466.2 465.5 4 235 2.44 452.2451.6 4 236 2.46 452.2 451.6 4 237 2.42 470.2 469.6 4 238 2.39 482.2481.6 4 239 2.64 502.2 501.6 4 240 2.68 532.2 531.7 4 241 2.22 503.2502.6 4 242 2.45 466.2 465.6 4 243 2.50 466.2 465.6 4 244 2.57 480.2479.6 4 245 2.48 454.2 453.6 4 246 2.42 473.1 450.6 4 247 2.24 503.2502.6 4 248 2.52 537.2 537.1 4 249 2.48 503.2 502.6 4 250 2.53 492.2491.6 4 251 2.59 508.2 507.7 4 252 2.74 516.2 515.7 4 253 2.48 496.2495.6 4 254 2.46 509.2 508.7 4 255 2.21 484.2 483.6 4 256 2.24 484.1483.6 4 257 2.19 502.2 501.6 4 258 2.16 514.2 513.6 4 259 2.46 534.2533.6 4 260 2.50 564.2 563.7 4 261 2.02 535.2 534.6 4 262 2.22 498.2497.6 4 263 2.29 498.2 497.6 4 264 2.38 512.2 511.6 4 265 2.26 486.2485.6 4 266 2.19 483.1 482.6 4 267 2.04 535.2 534.6 4 268 2.33 569.1569.1 4 269 2.27 535.2 534.6 4 270 2.33 524.2 523.6 4 271 2.41 540.1539.7 4 272 2.57 548.2 547.7 4 273 2.27 528.2 527.6 4 274 2.24 541.1540.7 4 275 2.00 473.2 472.5 4 276 0.774 501 500.5457 3 277 0.816 535534.9908 3 278 0.67 502 501.5338 3 279 0.871 569 568.5437 3 280 0.714451 450.487 3 281 0.717 453 452.5029 3 282 0.75 502 501.5338 3 283 0.84515 514.5723 3 284 0.805 519 518.5362 3 285 0.719 483 482.5289 3 2860.753 502 501.5338 3 287 0.763 491 490.5078 3 288 0.988 491 492.4477 3289 0.785 507 506.5734 3 290 2.24 450.1 427.5 4 291 2.19 428.1 427.5 4292 2.15 446.1 445.5 4 293 2.20 458.2 457.5 4 294 2.42 478.2 477.6 4 2952.45 508.1 507.6 4 296 2.09 479.1 478.6 4 297 2.22 479.1 478.6 4 2982.28 468.1 467.5 4 299 2.39 482.1 481.6 4 300 2.45 458.2 457.6 4 3012.47 458.2 457.6 4 302 2.43 476.2 475.6 4 303 2.40 488.1 487.6 4 3042.65 508.2 507.7 4 305 2.67 538.2 537.7 4 306 2.26 509.1 508.7 4 3072.49 509.1 508.7 4 308 2.53 498.2 497.6 4 309 2.73 500.1 499.6 4 3102.62 512.2 511.7 4 311 2.23 490.2 489.6 4 312 2.25 490.2 489.6 4 3132.21 508.1 507.6 4 314 2.17 520.1 519.6 4 315 2.45 540.2 539.7 4 3162.50 570.1 569.7 4 317 2.04 541.1 540.7 4 318 2.28 489.1 488.6 4 3192.05 541.2 540.7 4 320 2.28 541.1 540.7 4 321 2.33 530.2 529.6 4 3222.18 542.1 541.6 4 323 2.43 544.2 543.7 4 324 2.09 423.2 422.5 4 3252.06 441.2 440.5 4 326 2.03 453.2 452.5 4 327 2.34 473.2 472.5 4 3282.37 503.2 502.6 4 329 1.92 474.2 473.5 4 330 1.94 474.2 473.5 4 3312.14 474.2 473.5 4 332 2.20 463.2 462.5 4 333 2.20 465.2 464.4 4 3342.30 477.3 476.5 4 335 2.35 453.2 452.6 4 336 2.38 453.2 452.6 4 3372.36 471.1 470.6 4 338 2.31 483.3 482.6 4 339 2.58 503.2 502.6 4 3402.61 533.2 532.7 4 341 2.18 504.2 503.6 4 342 2.35 452.1 451.5 4 3432.41 504.2 503.6 4 344 2.46 493.2 492.6 4 345 2.48 495.2 494.5 4 3462.33 505.2 504.6 4 347 2.56 507.2 506.6 4 348 2.13 485.2 484.6 4 3492.12 503.2 502.6 4 350 2.08 515.2 514.6 4 351 2.39 535.2 534.6 4 3522.43 565.2 564.7 4 353 2.19 536.2 535.6 4 354 2.25 525.2 524.6 4 3552.26 527.1 526.5 4 356 2.10 537.2 536.6 4 357 2.36 539.2 538.6 4 3582.03 427.2 426.5 4 359 2.19 485.2 484.6 4 360 2.13 480.2 479.6 4 3612.10 423.3 422.5 4 362 2.11 480.2 479.6 4 363 2.06 475.2 474.5 4 3642.24 509.2 508.7 4 365 2.47 515.2 514.7 4 366 2.40 510.2 509.6 4 3672.19 504.2 503.6 4 368 2.39 510.2 509.6 4 369 2.25 547.2 546.7 4 3702.16 485.2 484.6 4 371 1.98 536.3 535.6 4 372 2.10 484.1 483.5 4 3731.99 536.3 535.6 4 374 2.16 542.2 541.6 4 375 1.443 370.1 369.33 1 3761.389 340 339.349 2 377 1.864 382.1 381.386 1 378 2.38 435.2 434.5 5 3792.40 435.2 434.5 5 380 2.37 453.2 452.5 5 381 2.34 465.2 464.5 5 3822.60 485.2 484.5 5 383 2.63 515.2 514.6 5 384 2.39 449.2 448.5 5 3852.44 449.2 448.5 5 386 2.52 463.2 462.5 5 387 2.43 437.2 436.5 5 3882.20 486.2 485.5 5 389 2.48 520.2 520.0 5 390 2.42 486.2 485.5 5 3912.48 475.2 474.5 5 392 2.55 491.2 490.6 5 393 2.70 499.3 498.6 5 3942.43 479.2 478.5 5 395 2.40 492.2 491.6 5 396 2.24 406.2 405.4 5 3972.26 406.2 405.4 5 398 2.22 424.2 423.5 5 399 2.20 436.2 435.5 5 4002.49 456.2 455.5 5 401 2.53 486.2 485.5 5 402 2.05 457.2 456.5 5 4032.25 420.3 419.5 5 404 2.31 420.3 419.5 5 405 2.41 434.2 433.5 5 4062.30 408.1 407.5 5 407 2.07 457.1 456.5 5 408 2.36 491.1 490.9 5 4092.29 457.2 456.5 5 410 2.35 446.2 445.5 5 411 2.43 462.2 461.5 5 4122.59 470.2 469.5 5 413 2.29 450.3 449.5 5 414 2.27 463.2 462.5 5 4152.18 486.1 485.5 5

BIOLOGIC EXAMPLE Example 13

In-Vitro Susceptibility Testing of Representative Compounds

The Minimum inhibitory concentrations (MIC) of compounds according tothe invention for a number of veterinary bacterial pathogens weredetermined by the broth-microdilution method according to CLSI documentVET01-A4.

Microdilution trays containing a doubling dilution series of the testcompound were used for the tests. The MIC results were interpretedaccording to the CLSI documents VET01-S3. The lowest concentration ofcompound at which no visible growth (i.e. no turbidity) detected by theunaided eye was recorded as the MIC.

Results

MIC Data for representative compounds is shown in Table 1 below.

The following pathogens/strains were tested:

ID Species Ext. RefNo. Remarks MH 6357 Mannheimia haemolytica M7/2Reference strain (cattle infection strain) MH 6374 Mannheimiahaemolytica ATCC 33396 Reference strain MH 10720 Mannheimia haemolytica154 BRD field isolate MH 12587 Mannheimia haemolytica 1071 BRD fieldisolate, macrolide- resistance: erm+, E+ MH 13065 Mannheimia haemolyticaXB0446-6003.9 BRD field isolate MH 13093 Mannheimia haemolyticaXB0472-6014.1 BRD field isolate PM 6267 Pasteurella multocida P 2225(L386) Reference strain (mouse infection strain) PM 6391 Pasteurellamultocida ATCC 43137 Reference strain PM 10775 Pasteurella multocida080130003051 BRD field isolate PM 12080 Pasteurella multocidaIV102277-0093 BRD field isolate

MH MH MH MH MH MH PM PM PM PM No 6357 6374 10720 12587 13065 13093 62676391 10775 12080 26 12.5 6.3 3.1 25 12.5 12.5 3.1 NT 0.8 6.3 27 12.512.5 3.1 25 25 25 3.1 NT 0.8 6.3 32 6.3 6.3 3.1 12.5 6.3 6.3 1.6 NT 0.43.1 40 6.3 3.1 6.3 12.5 6.3 6.3 3.1 NT 0.8 6.3 43 6.3 6.3 1.6 12.5 6.312.5 3.1 NT 0.4 3.1 46 6.3 6.3 1.6 12.5 6.3 6.3 1.6 NT 0.2 6.3 49 12.512.5 6.3 25 12.5 12.5 3.1 NT 0.8 12.5 71 1.6 0.8 0.4 1.6 0.8 3.1 0.2 NT<=0.1 0.4 72 12.5 12.5 6.3 25 12.5 12.5 1.6 NT 0.8 12.5 73 3.1 3.1 3.16.3 3.1 3.1 0.4 NT <=0.1 1.6 74 3.1 3.1 3.1 12.5 6.3 12.5 0.8 NT <=0.13.1 76 12.5 25 6.3 25 12.5 25 0.4 NT 0.2 3.1 77 6.3 1.6 0.8 3.1 3.1 3.1<=0.1 NT <=0.1 0.8 78 6.3 6.3 3.1 12.5 6.3 6.3 <=0.1 NT <=0.1 0.8 7912.5 25 3.1 25 12.5 25 0.4 NT <=0.1 1.6 80 1.6 1.6 0.8 3.1 1.6 6.3 <=0.1NT <=0.1 0.8 81 3.1 3.1 0.8 25 3.1 6.3 <=0.1 NT <=0.1 0.8 82 1.6 0.8 0.43.1 6.3 3.1 <=0.1 NT <=0.1 0.8 83 25 0.8 0.4 1.6 0.8 1.6 <=0.1 NT <=0.10.8 84 3.1 3.1 0.8 3.1 3.1 3.1 <=0.1 NT <=0.1 0.4 85 3.1 0.8 1.6 3.1 1.63.1 <=0.1 NT <=0.1 0.8 86 1.6 0.8 0.4 3.1 1.6 3.1 <=0.1 NT <=0.1 0.8 873.1 0.8 1.6 6.3 3.1 3.1 0.2 NT <=0.1 1.6 88 6.3 1.6 1.6 6.3 3.1 12.5 0.2NT <=0.1 1.6 89 6.3 3.1 1.6 12.5 6.3 6.3 0.4 NT <=0.1 1.6 90 3.1 1.6 1.63.1 1.6 1.6 <=0.1 NT <=0.1 0.8 91 6.3 3.1 1.6 12.5 6.3 12.5 0.4 NT <=0.11.6 92 0.8 <=0.1 <=0.1 0.2 <=0.1 0.2 <=0.1 NT <=0.1 <=0.1 93 6.3 6.3 3.112.5 6.3 12.5 <=0.1 NT <=0.1 1.6 94 12.5 0.8 0.8 1.6 0.8 1.6 <=0.1 NT<=0.1 0.8 95 1.6 3.1 0.8 6.3 3.1 3.1 <=0.1 NT <=0.1 0.4 96 3.1 0.8 0.812.5 1.6 3.1 0.2 NT <=0.1 0.8 97 12.5 12.5 3.1 12.5 12.5 12.5 0.2 NT<=0.1 0.8 98 0.8 1.6 0.4 1.6 1.6 1.6 <=0.1 NT <=0.1 <=0.1 99 3.1 6.3 0.812.5 6.3 6.3 <=0.1 NT <=0.1 0.2 100 3.1 6.3 0.8 12.5 3.1 6.3 0.4 NT<=0.1 0.8 101 3.1 3.1 0.8 12.5 3.1 3.1 0.4 NT <=0.1 0.8 102 3.1 3.1 0.812.5 3.1 6.3 0.4 NT <=0.1 0.8 104 0.4 0.4 <=0.1 1.6 0.4 0.8 <=0.1 NT<=0.1 0.4 105 6.3 3.1 0.8 6.3 3.1 3.1 0.2 NT <=0.1 0.8 106 0.8 0.8 0.21.6 0.8 1.6 0.2 NT <=0.1 0.8 107 3.1 0.8 0.4 3.1 0.8 0.8 0.2 NT <=0.10.4 108 3.1 1.6 1.6 3.1 1.6 3.1 0.4 NT <=0.1 1.6 110 1.6 0.4 <=0.1 0.80.4 0.4 <=0.1 NT <=0.1 0.2 111 3.1 3.1 0.8 12.5 3.1 3.1 0.8 NT 0.4 1.6112 1.6 0.4 <=0.1 0.8 0.4 0.4 <=0.1 NT <=0.1 0.2 113 3.1 0.8 0.4 3.1 1.63.1 0.4 NT <=0.1 0.8 114 6.3 12.5 1.6 12.5 6.3 6.3 0.2 NT <=0.1 0.8 1156.3 1.6 0.8 6.3 3.1 3.1 0.4 NT <=0.1 1.6 116 25 25 3.1 1 25 25 0.8 NT0.4 3.1 118 6.3 12.5 3.1 25 12.5 12.5 0.4 NT 0.2 1.6 119 1.6 1.6 0.4 3.11.6 3.1 <=0.1 NT <=0.1 <=0.1 124 6.3 12.5 3.1 25 12.5 12.5 3.1 NT 0.83.1 126 3.1 1.6 0.4 1.6 1.6 1.6 0.4 NT <=0.1 0.8 127 3.1 6.3 1.6 25 6.312.5 1.6 NT 0.4 1.6 128 3.1 3.1 0.8 12.5 3.1 6.3 3.1 NT 0.4 3.1 129 1.61.6 0.4 3.1 1.6 3.1 0.8 NT <=0.1 1.6 130 3.1 3.1 1.6 12.5 6.3 6.3 3.1 NT0.4 3.1 132 1.6 0.8 0.2 0.8 0.8 0.8 <=0.1 NT <=0.1 0.4 134 25 6.3 6.312.5 12.5 25 0.8 NT <=0.1 3.1 135 3.1 6.3 0.8 1 25 25 0.8 NT <=0.1 0.8136 3.1 12.5 1.6 25 12.5 25 0.4 0.8 <=0.1 0.8 141 6.3 12.5 1.6 12.5 6.312.5 1.6 3.1 0.2 3.1 142 6.3 12.5 3.1 25 12.5 12.5 0.2 0.4 <=0.1 0.4 1446.3 12.5 1.6 25 12.5 12.5 3.1 12.5 0.4 3.1 145 6.3 25 3.1 25 12.5 12.53.1 6.3 0.2 6.3 146 6.3 25 1.6 25 12.5 25 0.8 1.6 <=0.1 <=0.1 147 3.16.3 3.1 6.3 6.3 6.3 0.4 1.6 <=0.1 1.6 148 6.3 25 1.6 25 12.5 12.5 0.81.6 <=0.1 1.6 149 12.5 25 3.1 25 25 25 0.8 1.6 <=0.1 1.6 150 6.3 25 3.125 12.5 25 6.3 25 <=0.1 <=0.1 151 6.3 25 3.1 25 12.5 25 3.1 12.5 <=0.16.3 152 3.1 25 3.1 12.5 12.5 12.5 1.6 6.3 0.2 3.1 153 12.5 25 6.3 2512.5 25 1.6 6.3 <=0.1 0.8 154 3.1 12.5 1.6 12.5 6.3 6.3 0.2 1.6 <=0.10.8 155 12.5 12.5 1.6 25 12.5 25 <=0.1 0.4 <=0.1 0.4 156 6.3 6.3 1.612.5 12.5 12.5 0.8 1.6 <=0.1 1.6 157 1.6 1.6 0.8 6.3 3.1 6.3 0.4 0.8<=0.1 0.8 158 1.6 3.1 0.8 6.3 6.3 6.3 0.4 0.8 <=0.1 0.8 159 1.6 1.6 0.43.1 3.1 3.1 0.2 0.8 <=0.1 0.4 160 0.8 0.8 0.4 3.1 1.6 3.1 <=0.1 0.4<=0.1 0.2 161 1.6 1.6 0.8 6.3 3.1 6.3 0.2 0.8 <=0.1 0.2 162 6.3 12.5 3.112.5 12.5 12.5 0.8 3.1 <=0.1 1.6 164 6.3 12.5 1.6 25 12.5 25 0.4 1.6<=0.1 1.6 165 6.3 12.5 3.1 25 12.5 12.5 <=0.1 0.2 <=0.1 <=0.1 166 3.16.3 0.8 6.3 6.3 6.3 0.2 0.8 <=0.1 0.4 167 0.4 0.4 <=0.1 0.8 0.8 0.8<=0.1 0.4 <=0.1 0.2 168 0.4 0.8 0.2 1.6 0.8 0.8 <=0.1 0.4 <=0.1 0.2 1690.4 0.8 0.2 1.6 0.8 0.8 <=0.1 0.4 <=0.1 0.4 170 0.2 0.4 <=0.1 0.4 0.40.4 <=0.1 0.4 <=0.1 0.2 171 0.2 0.4 <=0.1 0.8 0.2 0.4 <=0.1 0.2 <=0.1<=0.1 172 0.4 0.8 0.4 1.6 0.8 0.8 0.2 0.4 <=0.1 0.4 173 3.1 3.1 0.8 6.36.3 6.3 <=0.1 0.8 <=0.1 0.4 174 3.1 6.3 0.8 6.3 6.3 6.3 0.4 1.6 <=0.11.6 175 6.3 12.5 3.1 25 12.5 12.5 0.4 1.6 <=0.1 0.8 176 3.1 6.3 3.1 12.56.3 12.5 0.8 3.1 <=0.1 1.6 177 3.1 6.3 1.6 12.5 6.3 6.3 0.8 3.1 <=0.11.6 178 1.6 3.1 0.8 6.3 1.6 3.1 0.2 0.8 <=0.1 0.4 179 0.4 0.8 <=0.1 1.60.8 0.8 0.2 1.6 <=0.1 0.4 180 0.8 1.6 0.2 3.1 1.6 1.6 0.4 1.6 <=0.1 0.8181 0.4 0.8 <=0.1 1.6 0.8 0.8 0.4 0.8 <=0.1 0.4 182 0.4 1.6 0.2 1.6 0.80.8 0.2 0.8 <=0.1 0.2 183 1.6 3.1 0.8 1.6 3.1 3.1 0.4 1.6 <=0.1 0.8 18412.5 6.3 0.8 12.5 6.3 6.3 0.4 3.1 <=0.1 1.6 185 3.1 6.3 0.8 6.3 3.1 6.3<=0.1 0.8 <=0.1 0.4 186 1.6 6.3 1.6 6.3 3.1 3.1 <=0.1 0.4 <=0.1 0.2 1873.1 12.5 1.6 12.5 6.3 6.3 0.4 1.6 <=0.1 0.8 188 0.8 1.6 <=0.1 3.1 0.80.8 <=0.1 NT <=0.1 <=0.1 189 1.6 3.1 NT 3.1 1.6 3.1 0.2 NT <=0.1 0.4 1901.6 3.1 0.4 3.1 1.6 1.6 <=0.1 0.4 <=0.1 0.2 191 6.3 25 1.6 25 6.3 12.5<=0.1 <=0.1 <=0.1 <=0.1 192 0.8 1.6 0.2 3.1 0.8 0.8 <=0.1 NT <=0.1 <=0.1193 6.3 6.3 0.8 6.3 3.1 3.1 0.4 0.8 <=0.1 0.4 194 6.3 25 NT 25 6.3 12.50.4 1.6 <=0.1 1.6 195 6.3 12.5 1.6 12.5 6.3 12.5 0.2 0.8 <=0.1 0.4 1966.3 12.5 1.6 12.5 6.3 12.5 0.2 0.8 <=0.1 0.4 197 1.6 3.1 0.4 6.3 1.6 3.1<=0.1 0.4 <=0.1 0.2 198 3.1 6.3 0.8 12.5 3.1 6.3 <=0.1 0.4 <=0.1 0.2 1990.2 0.4 <=0.1 0.4 0.2 0.4 <=0.1 <=0.1 <=0.1 <=0.1 200 6.3 3.1 0.8 6.31.6 3.1 <=0.1 0.2 <=0.1 0.2 201 12.5 6.3 3.1 12.5 6.3 6.3 0.4 0.8 <=0.10.4 202 0.8 3.1 0.2 3.1 1.6 1.6 <=0.1 NT <=0.1 <=0.1 203 1.6 1.6 0.2 3.10.8 1.6 <=0.1 NT <=0.1 <=0.1 204 0.4 0.4 <=0.1 0.8 0.2 0.4 <=0.1 NT<=0.1 <=0.1 205 1.6 3.1 0.8 6.3 1.6 3.1 0.2 0.4 <=0.1 0.4 206 3.1 3.10.8 6.3 3.1 6.3 <=0.1 0.4 <=0.1 0.2 207 12.5 12.5 3.1 12.5 6.3 12.5 0.20.8 <=0.1 0.8 208 12.5 12.5 3.1 25 12.5 12.5 0.2 0.4 <=0.1 0.2 209 3.16.3 1.6 12.5 6.3 12.5 <=0.1 0.4 <=0.1 0.2 210 1.6 3.1 0.8 6.3 1.6 3.1<=0.1 0.2 <=0.1 <=0.1 211 3.1 12.5 1.6 12.5 6.3 6.3 <=0.1 0.2 <=0.1<=0.1 212 3.1 6.3 0.8 12.5 3.1 12.5 0.2 0.4 <=0.1 0.2 213 1.6 1.6 0.83.1 1.6 3.1 <=0.1 0.4 <=0.1 0.2 214 1.6 1.6 0.8 6.3 3.1 3.1 0.2 0.4<=0.1 0.4 215 3.1 3.1 0.8 6.3 3.1 6.3 <=0.1 <=0.1 <=0.1 <=0.1 216 1.63.1 0.8 3.1 1.6 3.1 <=0.1 0.2 <=0.1 0.2 218 0.4 0.4 <=0.1 0.8 0.4 0.40.4 NT NT <=0.1 219 1.6 0.4 <=0.1 1.6 0.4 0.8 <=0.1 <=0.1 <=0.1 <=0.1220 3.1 0.8 <=0.1 3.1 0.8 1.6 <=0.1 0.4 <=0.1 0.4 221 0.8 0.8 <=0.1 3.11.6 1.6 <=0.1 0.4 <=0.1 0.4 222 0.8 1.6 0.2 1.6 1.6 1.6 <=0.1 <=0.1<=0.1 0.2 223 0.8 0.4 <=0.1 0.8 0.4 0.4 <=0.1 <=0.1 <=0.1 <=0.1 224 0.80.8 <=0.1 1.6 0.8 0.8 <=0.1 0.4 <=0.1 <=0.1 225 12.5 6.3 1.6 12.5 12.512.5 <=0.1 0.8 NT 0.8 226 3.1 3.1 0.8 12.5 3.1 6.3 <=0.1 0.4 <=0.1 0.4227 12.5 12.5 1.6 25 6.3 12.5 0.4 0.8 0.2 0.8 228 0.8 0.4 <=0.1 1.6 0.40.8 <=0.1 <=0.1 <=0.1 <=0.1 229 0.4 0.4 <=0.1 0.4 0.2 0.4 <=0.1 <=0.1<=0.1 <=0.1 230 0.8 0.4 <=0.1 1.6 0.8 0.8 <=0.1 <=0.1 <=0.1 <=0.1 2310.4 0.2 <=0.1 0.8 0.2 0.4 <=0.1 <=0.1 <=0.1 <=0.1 232 0.4 <=0.1 <=0.10.4 <=0.1 0.2 <=0.1 <=0.1 <=0.1 <=0.1 233 0.8 0.4 <=0.1 1.6 0.4 0.8<=0.1 0.2 <=0.1 <=0.1 234 6.3 3.1 0.4 6.3 3.1 6.3 <=0.1 0.4 <=0.1 0.2235 0.4 0.8 <=0.1 1.6 0.4 0.4 <=0.1 <=0.1 <=0.1 <=0.1 236 0.8 0.8 <=0.11.6 0.8 0.8 <=0.1 0.4 <=0.1 0.4 237 1.6 1.6 0.2 3.1 1.6 1.6 0.2 0.8<=0.1 0.4 238 1.6 3.1 0.8 3.1 1.6 1.6 <=0.1 <=0.1 <=0.1 <=0.1 239 0.81.6 0.2 1.6 0.8 0.8 0.2 0.4 <=0.1 0.4 240 1.6 1.6 0.4 1.6 1.6 1.6 0.20.8 0.2 0.4 241 0.4 0.8 <=0.1 0.8 0.4 0.4 <=0.1 <=0.1 <=0.1 <=0.1 2426.3 6.3 0.8 6.3 3.1 3.1 0.4 1.6 0.2 0.8 243 3.1 3.1 0.4 3.1 1.6 1.6 0.20.8 <=0.1 0.4 244 3.1 6.3 1.6 6.3 3.1 6.3 0.4 1.6 0.2 0.8 245 3.1 3.10.4 3.1 1.6 3.1 0.4 0.8 <=0.1 0.8 246 0.4 0.8 <=0.1 0.8 0.8 0.4 <=0.10.2 <=0.1 0.2 247 0.4 0.8 0.2 0.8 0.4 0.8 <=0.1 0.8 <=0.1 0.2 248 1.61.6 0.4 1.6 1.6 1.6 0.4 0.8 0.2 0.8 249 0.8 1.6 0.2 1.6 0.8 0.8 0.2 0.8<=0.1 0.4 250 0.4 0.8 <=0.1 0.8 0.4 0.4 <=0.1 0.2 <=0.1 <=0.1 251 0.80.8 <=0.1 1.6 0.8 0.8 <=0.1 0.2 <=0.1 <=0.1 252 1.6 3.1 0.4 3.1 1.6 1.60.4 0.8 0.4 0.8 253 3.1 3.1 0.8 3.1 1.6 3.1 <=0.1 0.4 <=0.1 0.4 254 0.81.6 0.2 1.6 0.8 0.8 <=0.1 0.4 <=0.1 <=0.1 255 0.8 0.4 <=0.1 1.6 0.4 0.8<=0.1 <=0.1 <=0.1 <=0.1 256 1.6 0.8 <=0.1 1.6 0.8 0.8 <=0.1 <=0.1 <=0.1<=0.1 257 3.1 1.6 0.4 3.1 1.6 1.6 <=0.1 0.2 <=0.1 <=0.1 258 1.6 1.6 0.21.6 0.8 1.6 <=0.1 <=0.1 <=0.1 <=0.1 259 0.8 0.4 <=0.1 0.8 0.4 0.8 <=0.1<=0.1 <=0.1 <=0.1 260 1.6 0.4 <=0.1 1.6 0.4 0.8 <=0.1 <=0.1 <=0.1 <=0.1261 0.4 0.4 <=0.1 0.8 0.4 0.4 <=0.1 <=0.1 <=0.1 <=0.1 262 12.5 6.3 1.612.5 6.3 6.3 <=0.1 0.4 <=0.1 0.4 263 6.3 3.1 0.8 6.3 3.1 3.1 <=0.1 0.4<=0.1 0.2 264 12.5 12.5 1.6 12.5 6.3 6.3 0.2 0.8 <=0.1 0.4 265 6.3 6.30.8 6.3 3.1 3.1 <=0.1 0.8 <=0.1 0.4 266 0.8 0.4 <=0.1 1.6 0.8 0.8 <=0.1<=0.1 <=0.1 <=0.1 267 0.8 0.4 <=0.1 1.6 0.8 0.8 <=0.1 <=0.1 <=0.1 <=0.1268 0.4 0.4 <=0.1 0.8 0.2 0.4 <=0.1 <=0.1 <=0.1 <=0.1 269 1.6 0.4 <=0.11.6 1.6 0.8 <=0.1 <=0.1 <=0.1 <=0.1 270 0.8 0.2 <=0.1 0.8 0.2 0.4 <=0.1<=0.1 <=0.1 <=0.1 271 0.4 0.2 <=0.1 0.8 0.2 0.4 <=0.1 <=0.1 <=0.1 <=0.1272 0.8 0.4 <=0.1 1.6 0.2 0.8 <=0.1 0.2 <=0.1 <=0.1 273 6.3 3.1 0.8 6.33.1 6.3 <=0.1 0.2 <=0.1 <=0.1 274 0.2 0.2 <=0.1 0.4 0.2 0.2 <=0.1 <=0.1<=0.1 <=0.1 275 0.4 0.2 <=0.1 0.4 0.2 0.4 <=0.1 <=0.1 <=0.1 <=0.1 2760.8 0.8 <=0.1 0.8 0.4 0.8 <=0.1 0.4 <=0.1 <=0.1 277 1.6 1.6 0.4 3.1 1.61.6 0.4 0.8 <=0.1 0.4 278 0.4 0.4 <=0.1 0.8 0.4 0.4 <=0.1 <=0.1 <=0.1<=0.1 279 3.1 6.3 1.6 6.3 6.3 6.3 0.4 1.6 0.4 1.6 280 1.6 0.8 <=0.1 3.11.6 1.6 <=0.1 0.4 <=0.1 0.2 282 0.8 0.8 <=0.1 1.6 0.4 1.6 0.8 0.4 0.40.2 283 3.1 3.1 0.2 6.3 1.6 3.1 3.1 1.6 0.2 0.8 284 0.4 0.8 <=0.1 1.60.2 0.8 0.8 0.4 <=0.1 <=0.1 285 1.6 3.1 <=0.1 6.3 1.6 3.1 3.1 1.6 <=0.10.8 286 0.4 0.8 <=0.1 1.6 0.4 0.8 0.8 0.8 <=0.1 <=0.1 287 0.4 0.8 <=0.11.6 0.8 0.8 0.8 0.4 <=0.1 <=0.1 288 0.4 0.8 <=0.1 0.8 0.4 0.8 0.4 <=0.1<=0.1 <=0.1 289 0.4 0.8 <=0.1 1.6 0.8 0.8 0.8 0.4 0.4 <=0.1 290 <=0.1<=0.1 <=0.1 0.4 <=0.1 0.2 <=0.1 0.2 <=0.1 <=0.1 291 <=0.1 <=0.1 <=0.10.8 0.4 0.4 0.8 0.4 <=0.1 <=0.1 292 0.4 0.8 <=0.1 1.6 0.8 1.6 1.6 0.8<=0.1 0.4 293 0.4 0.8 <=0.1 0.8 0.4 0.8 1.6 0.2 <=0.1 <=0.1 294 <=0.10.2 <=0.1 0.4 <=0.1 0.4 0.8 0.2 <=0.1 <=0.1 295 <=0.1 0.4 <=0.1 0.8 0.20.4 0.8 0.4 <=0.1 <=0.1 296 <=0.1 0.2 <=0.1 0.4 <=0.1 0.4 0.8 <=0.1<=0.1 <=0.1 297 0.2 0.4 <=0.1 0.8 0.4 0.4 0.4 <=0.1 <=0.1 0.2 298 <=0.10.2 <=0.1 0.4 0.2 0.4 0.4 <=0.1 <=0.1 <=0.1 299 0.2 0.4 <=0.1 0.8 0.40.4 0.4 <=0.1 <=0.1 0.4 300 0.4 0.8 <=0.1 0.8 0.4 0.8 0.4 <=0.1 <=0.10.4 301 0.4 0.8 <=0.1 0.8 0.4 0.8 0.4 1.6 <=0.1 0.4 302 0.4 0.8 <=0.11.6 0.8 0.8 0.8 0.8 <=0.1 0.4 303 0.2 1.6 0.4 1.6 1.6 1.6 1.6 0.4 <=0.10.4 304 0.8 1.6 <=0.1 1.6 1.6 3.1 1.6 1.6 <=0.1 0.4 305 0.8 0.8 0.2 3.10.8 1.6 0.8 0.4 <=0.1 0.4 306 0.8 0.8 0.2 3.1 0.8 0.8 0.8 0.4 <=0.1 0.4307 0.8 0.8 <=0.1 1.6 0.8 1.6 0.8 0.4 <=0.1 0.4 308 0.8 0.8 <=0.1 1.60.8 1.6 0.8 0.4 <=0.1 0.4 309 0.8 0.8 <=0.1 1.6 0.8 1.6 1.6 0.4 <=0.10.4 310 1.6 0.8 0.4 3.1 1.6 1.6 1.6 0.4 0.4 0.8 311 0.2 <=0.1 <=0.1 0.4<=0.1 0.4 0.4 <=0.1 <=0.1 <=0.1 312 0.4 0.4 <=0.1 0.8 0.4 0.8 0.4 <=0.1<=0.1 <=0.1 313 0.4 1.6 <=0.1 1.6 0.4 0.8 0.2 <=0.1 <=0.1 <=0.1 314 0.41.6 <=0.1 0.8 0.4 0.8 0.4 <=0.1 <=0.1 <=0.1 315 <=0.1 <=0.1 <=0.1 0.4<=0.1 0.4 0.2 <=0.1 <=0.1 <=0.1 316 <=0.1 0.2 <=0.1 0.8 0.2 0.4 0.2<=0.1 <=0.1 <=0.1 317 0.2 0.4 <=0.1 0.8 0.4 0.4 0.2 <=0.1 <=0.1 <=0.1318 0.4 0.8 <=0.1 1.6 0.8 1.6 0.8 0.8 <=0.1 0.2 319 0.2 0.2 <=0.1 0.80.4 0.4 0.2 <=0.1 <=0.1 <=0.1 320 0.2 <=0.1 <=0.1 0.8 0.2 0.4 0.2 <=0.1<=0.1 <=0.1 321 <=0.1 <=0.1 <=0.1 0.4 0.2 0.2 <=0.1 <=0.1 <=0.1 <=0.1322 0.4 1.6 <=0.1 1.6 0.8 0.8 0.4 0.2 <=0.1 <=0.1 323 0.2 0.2 <=0.1 0.80.4 0.8 0.2 <=0.1 <=0.1 <=0.1 324 0.4 0.8 <=0.1 1.6 0.8 1.6 0.4 0.4<=0.1 0.2 325 0.8 1.6 0.4 3.1 1.6 3.1 1.6 0.8 <=0.1 0.8 326 3.1 6.3 0.812.5 3.1 6.3 3.1 0.4 <=0.1 0.4 327 0.8 0.8 <=0.1 1.6 0.4 0.8 0.4 <=0.1<=0.1 <=0.1 328 0.8 0.8 <=0.1 1.6 0.8 0.8 0.8 <=0.1 <=0.1 <=0.1 329 0.81.6 <=0.1 3.1 0.8 1.6 0.8 0.4 <=0.1 0.4 330 0.8 0.8 0.2 3.1 1.6 1.6 1.60.8 <=0.1 0.4 331 1.6 3.1 0.4 6.3 3.1 6.3 3.1 1.6 0.4 1.6 332 0.4 0.4<=0.1 1.6 0.8 0.8 0.4 0.4 <=0.1 0.2 333 0.4 0.8 <=0.1 1.6 0.8 1.6 0.40.4 <=0.1 0.2 334 0.4 0.4 <=0.1 1.6 0.8 1.6 0.4 0.4 <=0.1 0.2 335 0.40.8 <=0.1 3.1 0.4 0.8 0.4 0.4 <=0.1 0.2 336 0.8 0.8 0.2 3.1 1.6 1.6 0.81.6 <=0.1 0.8 337 3.1 3.1 0.8 6.3 6.3 3.1 3.1 1.6 0.2 0.8 338 3.1 6.30.8 6.3 3.1 6.3 3.1 0.8 <=0.1 0.4 339 0.8 1.6 <=0.1 1.6 0.8 1.6 0.8 0.8<=0.1 0.2 340 0.8 1.6 0.4 3.1 1.6 1.6 1.6 1.6 0.2 0.8 341 0.8 1.6 0.23.1 1.6 1.6 1.6 0.8 0.2 0.4 342 1.6 3.1 0.4 6.3 3.1 3.1 1.6 1.6 0.2 0.8343 3.1 3.1 0.4 6.3 3.1 6.3 3.1 6.3 0.4 1.6 344 0.4 0.8 <=0.1 1.6 0.81.6 0.8 0.8 <=0.1 0.4 345 0.8 1.6 <=0.1 1.6 0.8 1.6 0.8 0.8 <=0.1 0.4346 6.3 6.3 0.8 12.5 6.3 12.5 6.3 3.1 0.4 1.6 347 0.8 1.6 0.2 3.1 1.61.6 1.6 0.8 <=0.1 0.8 348 0.8 0.8 <=0.1 3.1 0.8 0.8 0.8 <=0.1 <=0.1<=0.1 349 1.6 3.1 0.8 6.3 6.3 3.1 1.6 0.8 <=0.1 0.4 350 6.3 6.3 1.6 12.56.3 6.3 6.3 0.8 <=0.1 0.4 351 0.4 0.4 <=0.1 1.6 1.6 0.8 0.4 0.4 <=0.1<=0.1 352 0.8 0.8 0.2 3.1 1.6 1.6 0.8 0.4 <=0.1 0.2 353 3.1 6.3 0.8 12.56.3 6.3 3.1 1.6 0.4 0.8 354 0.4 0.8 0.2 1.6 1.6 0.8 0.8 0.4 <=0.1 0.2355 0.8 1.6 <=0.1 1.6 0.8 1.6 0.8 0.2 <=0.1 <=0.1 356 6.3 6.3 3.1 12.56.3 12.5 6.3 3.1 0.2 1.6 357 0.8 0.8 <=0.1 1.6 0.8 1.6 0.8 0.4 <=0.1 0.2358 3.1 1.6 0.8 6.3 6.3 6.3 0.8 1.6 0.2 0.8 359 0.4 0.2 <=0.1 0.4 0.20.4 <=0.1 <=0.1 0.2 <=0.1 360 0.8 1.6 0.8 6.3 1.6 6.3 0.4 1.6 <=0.1 0.4361 3.1 0.8 0.4 3.1 1.6 3.1 0.4 0.4 <=0.1 0.2 362 3.1 0.8 0.4 3.1 1.63.1 0.2 0.4 <=0.1 0.2 363 6.3 6.3 3.1 25 12.5 25 1.6 3.1 0.4 1.6 364 0.80.8 0.2 1.6 0.8 0.8 0.4 0.4 <=0.1 <=0.1 365 0.8 0.8 0.2 3.1 1.6 1.6 0.40.4 <=0.1 <=0.1 366 0.8 0.8 0.2 1.6 0.8 1.6 0.4 0.4 <=0.1 0.2 367 0.80.8 0.4 3.1 1.6 3.1 0.4 0.4 <=0.1 0.2 368 0.8 0.8 0.4 1.6 0.8 1.6 0.40.4 <=0.1 0.2 369 0.4 0.2 <=0.1 0.4 0.4 0.4 <=0.1 <=0.1 <=0.1 <=0.1 3700.8 1.6 0.8 3.1 1.6 3.1 0.2 0.4 <=0.1 0.2 371 1.6 1.6 0.8 3.1 1.6 3.10.2 0.2 <=0.1 0.2 372 6.3 12.5 3.1 25 12.5 25 1.6 1.6 0.4 0.8 373 1.63.1 0.4 6.3 3.1 3.1 0.4 0.8 <=0.1 0.4 374 0.8 0.8 0.4 3.1 1.6 3.1 0.20.2 <=0.1 <=0.1 375 1.6 3.1 0.8 6.3 3.1 6.3 0.8 1.6 <=0.1 3.1 376 1.63.1 0.8 6.3 3.1 6.3 0.8 1.6 <=0.1 1.6 378 0.8 0.8 0.4 0.2 0.8 0.8 1.6<=0.1 0.4 0.2 379 0.8 1.6 0.8 0.4 1.6 1.6 3.1 <=0.1 0.4 0.4 380 3.1 6.33.1 0.8 3.1 6.3 6.3 0.2 1.6 0.8 381 1.6 3.1 0.4 1.6 1.6 1.6 1.6 <=0.10.2 0.2 382 0.8 1.6 0.8 0.2 0.8 0.8 0.8 <=0.1 0.4 0.4 383 0.8 1.6 0.80.4 1.6 1.6 6.3 <=0.1 0.8 0.4 384 6.3 12.5 3.1 1.6 6.3 6.3 12.5 0.4 3.11.6 385 3.1 6.3 1.6 1.6 3.1 6.3 25 0.2 0.8 0.4 386 12.5 12.5 1.6 1.612.5 12.5 50 0.4 1.6 0.4 387 6.3 6.3 3.1 1.6 6.3 3.1 25 0.4 1.6 0.2 3880.4 0.8 0.8 0.2 0.8 0.8 3.1 <=0.1 0.2 <=0.1 389 0.8 1.6 0.8 0.4 1.6 1.63.1 <=0.1 0.4 0.4 390 0.4 1.6 0.8 0.2 0.8 0.8 3.1 <=0.1 0.4 0.2 391 0.40.4 0.4 <=0.1 0.4 0.4 1.6 <=0.1 0.4 <=0.1 392 0.4 0.4 0.4 <=0.1 0.4 0.41.6 <=0.1 0.4 <=0.1 393 0.8 1.6 0.8 0.4 6.3 6.3 6.3 0.2 0.8 0.4 394 3.16.3 1.6 0.8 3.1 3.1 6.3 0.2 0.8 0.4 395 0.4 0.8 0.4 0.2 0.8 0.8 3.1<=0.1 0.2 0.2 396 1.6 1.6 1.6 0.4 3.1 3.1 12.5 <=0.1 0.8 0.4 398 6.3 6.36.3 1.6 12.5 25 25 0.2 3.1 1.6 399 3.1 6.3 1.6 1.6 6.3 6.3 25 <=0.1 0.80.4 400 0.8 1.6 1.6 0.2 1.6 1.6 3.1 <=0.1 0.8 0.4 401 1.6 1.6 3.1 0.41.6 1.6 6.3 0.2 1.6 0.8 402 6.3 12.5 6.3 1.6 6.3 6.3 50 0.8 3.1 1.6 40325 12.5 12.5 6.3 25 25 100 0.8 6.3 3.1 404 12.5 12.5 6.3 3.1 25 50 250.4 3.1 1.6 405 25 50 6.3 12.5 0.8 25 100 0.8 3.1 0.8 406 12.5 25 6.31.6 25 12.5 25 0.2 3.1 3.1 407 3.1 6.3 6.3 1.6 6.3 6.3 25 0.2 1.6 0.8408 1.6 1.6 1.6 0.4 1.6 1.6 6.3 <=0.1 0.8 0.4 410 0.8 1.6 1.6 0.4 1.61.6 6.3 <=0.1 0.8 0.4 411 0.4 0.8 0.8 0.2 0.8 0.8 3.1 <=0.1 0.4 0.2 4121.6 1.6 1.6 0.4 1.6 1.6 6.3 <=0.1 0.4 0.2 413 12.5 12.5 3.1 6.3 6.3 2550 0.2 0.4 0.4 414 0.8 1.6 0.8 0.4 0.8 1.6 6.3 <=0.1 0.4 <=0.1 415 0.40.8 0.4 0.2 0.4 0.4 1.6 <=0.1 <=0.1 <=0.1 NT = not tested

Example 14

In-Vitro Susceptibility Testing of Representative Compounds

The in vitro activity of representative compounds of the currentinvention are tested against bacterial isolates of different species:

The Minimum inhibitory concentrations (MIC) of compounds according tothe invention are determined by the broth-microdilution method accordingto CLSI document VET1-A4.

Microdilution trays containing a doubling dilution series of the testcompound are used for the tests.

The MIC results are interpreted according to the CLSI documentsVET01-S3. The lowest concentration of compound at which no visiblegrowth (i.e. no turbidity) detected by the unaided eye is recorded asthe MIC.

The following pathogens/strains are tested:

ID Species Ext. RefNo. Remarks MH 6357 Mannheimia haemolytica M7/2Reference strain (cattle infection strain) MH 6374 Mannheimiahaemolytica ATCC 33396 Reference strain PM 6267 Pasteurella multocida P2225 (L386) Reference strain (mouse infection strain) PM 6391Pasteurella multocida ATCC 43137 Reference strain SA 5816 Staphylococcusaureus 2139 Mastitis field isolate SA 6114 Staphylococcus aureus ATCC29213 Reference strain MH 10720 Mannheimia haemolytica 154 BRD fieldisolate MH 12180 Mannheimia haemolytica KLI-02944 BRD field isolate MH12587 Mannheimia haemolytica 1071 BRD field isolate, macrolide-resistance: erm+, E+ PM 10775 Pasteurella multocida 080130003051 BRDfield isolate PM 12080 Pasteurella multocida IV102277-0093 BRD fieldisolate PM 14426 Pasteurella multocida 0006-439 BRD field isolatemacrolide-resistant AB 15919 Acinetobacter baumanii IV369-2012Dermatitis field isolate AB 16496 Acinetobacter baumanii ATCC 19606Reference strain

Example 15

In Vitro Activity Against Bacteria Isolated from Respiratory Tract ofSwine and Cattle Suffering from Respiratory Disease Collected inDifferent European Countries

The in vitro activity of compounds against 20 isolates of Actinobacillus(A.) pleuropneumoniae, 20 of Bordetella (B.) bronchiseptica, 20 ofHistophilus (H.) somni, 40 of Mannheimia (M.) haemolytica and 40 ofPasteurella (P.) multocida collected in different European countries aredetermined. All bacteria are isolated from the respiratory tract ofswine and cattle suffering from respiratory disease. All isolates wereepidemiologically unrelated as specified by the different suppliers.

The minimum inhibitory concentrations (MIC) of compounds according tothe invention are determined by the broth-microdilution method accordingto CLSI document VET01-A4.

Microdilution trays containing a doubling dilution series of the testcompounds are used for the tests.

The MIC results are interpreted according to the CLSI documentsVET01-S3. The lowest concentration of compound at which no visiblegrowth (i.e. no turbidity) detected by the unaided eye is recorded asthe MIC. The MIC₅₀ and MIC₉₀ represent the concentration at whichminimum 50% or 90% of the isolates are inhibited.

Example 16

In Vitro Activity Haemophilus parasuis Isolated from the RespiratoryTract of Swine Suffering from Respiratory Disease

The in vitro activity of representative compounds of this inventionagainst 15 isolates of H. parasuis is determined. All strains areisolated from the respiratory tract of swine in different Europeancountries

The MICs for all isolates are determined by using the agar-dilutionmethod according to CLSI document VET01-A4 [1] with the followingmodification: GC agar base is used instead of Mueller-Hinton agar basefor the preparation of the agar-dilution plates.

Results are interpreted according to the CLSI document VET01-S3. The MICis the lowest concentration of antimicrobial agent that completelyinhibits colony formation, disregarding a single colony or a faint hazecaused by inoculum.

Example 17

Determination of the In-Vivo Efficacy in a Mouse Septicemia Model withPasteurella Multocida

The objective of this study was to determine the in-vivo efficacy ofantibiotic compounds after subcutaneous (SC) administration in asepticemia mouse model with Pasteurella (P.) multocida.

Materials and Methods

BALB/c mice were allocated to groups consisting of 6 mice. The mice ofall groups (excluding the uninfected control group) were infectedintraperitoneally (IP) with 3.2×10² CFU (colony forming units) P.multocida L386, Serotype A:14, per animal in 0.2 mL PBS.

Mice of the uninfected control group received 0.2 mL of sterilePhosphate Buffered Saline (PBS) intraperitoneally.

One hour after infection, the mice were treated subcutaneously with 10mg/kg bodyweight of a 1 mg/mL solution of compounds of the invention ina 10% solution of Captisol® in PBS. The negative control groups weretreated SC with 0.2 mL of galenic diluent only. In the positive controlgroup Enrofloxacin was used in a commercial formulation ad usumveterinarium (Baytril® 2.5%, Bayer Animal Health), that was diluted withphysiological saline for injection to achieve a concentration of 1 mg/mLand was administered at a dosage of 10 mg/kg bodyweight. The clinicaltime course of the infection was observed.

Survival of the mice was recorded at the end of the animal phase (D+2).At this timepoint all remaining mice were euthanized. From all animalsof this study, a liver tissue sample was taken for quantitativere-isolation of bacteria.

Results:

“Mouse survival” indicates the number of animals (x/6) that survived atthe end of the in-vivo phase (D+2)

“Bacteriological cured” indicates that no bacteria were re-isolated fromliver tissue (LOQ=100 CFU/g tissue). The following table 5-1 shows theresults for representative compounds of the invention.

TABLE 5-1 No of animals survived No of animals bacteriological cured 4of 6 5 of 6 6 of 6 2 of 6 3 of 6 4 of 6 5 of 6 6 of 6 C.236 C.236 C.237C.237 C.255 C.255 C.256 C.259 C.259 C.267 C.267 C.269 C.269 C.270 C.270C.274 C.274 C.261 C.261 C.292 C.292 C.311 C.311 C.313 C.313 C.319 C.319

Example 18

Antiinfective Efficacy of Subcutaneous Treatment in the Mannheimiahaemolytica Cattle Lung Infection Model

Material and Methods

15 male Holstein black pied cattle calves of ca. 4 months age arerandomly assigned to the study groups ensuring an equal distribution ofbody weight. The animal weight is approximately 98-133.5 kg on D-1.

Calves are infected on Day 0 via intratracheal instillation ofapproximately 300 mL of a M. haemolytica PBS suspension containingapproximately 3×10⁹ CFU M. haemolytica in late log phase.

Species Ref.-no. Serotype ID Origin/description M. haemolytica M7/2 A:16357 Isolate from cattle, United Kingdom

Three animals each are treated one hour after infection by subcutaneous(SC) administration of a compound of the invention in an aqueous 30%(w/v) Captisol® solution for injection at a dose of 10 mg/kg BW.

The respective dose volume is injected on the sides of the thoracicwall. Injection volumes exceeding 10 mL are divided into one portion of10 mL administered to the left side and the remaining rest administeredat different injection sites on the other side. Animals in one controlgroup are treated with a commercially available Enrofloxacin solution(Baytril® 10%, Bayer Animal Health) at the recommended dose of 10 mg/kgBW. The second control group is treated with the galenic diluent (30%(w/v) Captisol®, dissolved in water) as placebo.

Animals are observed for clinical parameters for two days. Foodconsumption is measured. Single individual blood samples are collectedfrom the 12 animals at the following time points: D-1 (predose), 30minutes, 2, 4, 6, 24 h and at D2 (ca. 45 h) after administration. Afterthe day 2 blood sampling, the infected cattle are slaughtered. The lungsare weighted. Lung states and lung scores are observed morphologically.

At necropsy from animals treated with test items or the positivecontrol, samples of epithelial lining fluid (ELF), lung tissue, andadditionally tissue of liver and kidney are collected. From each lungtwo bacteriological swaps are taken from the left and right bronchus.

Epithelial lining fluid is collected by inserting sterile paper stripscaudally behind the tracheal bifurcation directly onto the bronchialmucous membrane in the left and right bronchus and allowed to moistenwith bronchial fluid. The paper strip is left in place (resting on thebronchial mucosa) for approximately 1 minute before being placed backinto the plastic container.

From each lung two tissue samples are collected by clipping from atleast two locations, one from morphologically unchanged tissue, one fromthe edge of pathomorphologically changed areas.

Plasma, ELF, lung tissue and additional tissue samples are analyzed forconcentrations of Compound of the invention andEnrofloxacin/Ciprofloxacin respectively using a HPLC-MS/MS method.

Example 19 Antiinfective Efficacy of Subcutaneous Treatment in theMannheimia haemolytica Cattle Lung Infection Model

Unless otherwise described the study is conducted as described inExample 16.

Calves are infected via intratracheal instillation of appr. 300 mL of M.haemolytica PBS suspension containing approximately 4×10⁹ CFU M.haemolytica in late log phase on Day 0.

Three animals each are treated one hour after infection by a singlesubcutaneous injection with 10 mg/kg of Compound of the invention, F40(80 mg/mL in 10% Poloxamer 188).

Example 20

Antiinfective Efficacy of Subcutaneous Treatment in the Mannheimiahaemolytica Cattle Lung Infection Model

Material and Methods

Unless otherwise described the study was conducted as described inClinical Example 15

Calves are infected via intratracheal instillation of appr. 300 mL of M.haemolytica PBS suspension containing approximately 4×10⁹ CFU M.haemolytica in late log phase on Day 0.

One hour later three animals each are treated with 10 mg/kg of Compoundof the invention (80 mg/mL in 10% Poloxamer 188), . . . .

1. Compound according to the formula (I):

or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, wherein R¹ is selected from the group consisting of H,C(R¹¹R¹²R¹³), C(═O)R¹¹, —C(═NR¹⁴)R¹¹; R¹¹ is selected from the groupconsisting of H, and C₁₋₆-alkyl; R¹² is selected from the groupconsisting of H, C₁₋₆-alkyl, and C₁₋₆-alkyl substituted with asubstituent from the group consisting of —SR⁸, —OR⁹, —C(═O)OR⁹, —NR⁹R¹⁰,—SO₂NR⁹R¹⁰, —SO₂R⁸; R¹³ is selected from the group consisting of H,C₁₋₆-alkyl, aryl, —SR⁸, —OR⁹, —NR⁹R¹⁰, —SO₂R⁸, nitro, —C(═O)NR⁹R¹⁰, andC₁₋₆-alkyl substituted with a substituent selected from the groupconsisting of —SR⁸, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁸, nitro, cyano,—OR⁹, —C(═O)OR⁹, —NR⁹C(═NR¹⁴)NR⁹R¹⁰; or R¹³ and R² together with the Natom which R² is attached to, form a saturated or unsaturatedheterocycle having 3 to 6 ring atoms wherein 1 ring atom is N and 0, 1or 2 further ring atoms are selected from N, S, and O the rest of thering atoms being C; wherein when R¹³ is OH or NH₂ and R¹² is methyl thenR¹¹ cannot be H and when R¹³ is NH₂ and R¹² is methyl then R¹¹ cannot bemethyl; R¹⁴ is selected from the group consisting of H, C₁₋₆-alkyl,—OR⁹; R², R³ is selected from the group consisting of H, C₁₋₆-alkyl, andC₁₋₆-alkyl substituted with a substituent from the group consisting ofhalogen, hydroxyl, C₁₋₆-alkoxy, aryloxy, ester, thiol, C₁₋₆-alkyl,carbonyl, —SR⁸, —SO₂NR⁹R¹⁰, —SO₂R⁸, —C(═O)NR⁹R¹⁰, cyano, —NR⁹R¹⁰,—C(═O)OR⁹, aryl, heteroaryl, heterocycle, C₃₋₈-cycloalkyl; R⁴ isselected from the group consisting of H, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, —OR⁹, C(═O)OR⁹, C(═O)R⁸, aryl,heterocyclyl, heteroaryl, C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkylsubstituted with heteroaryl, C₁-C₆-alkyl substituted with heterocyclylwherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl,heteroaryl, is optionally substituted with a substituent selected fromthe group consisting of C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy,NR⁹R¹⁰, carbonyl, nitro, C(═O)OR⁹, halogen, halo-C₁₋₆-alkyl,C₁₋₆-alkyloxy-C₁₋₆-alkyl, cyano, hydroxy, —SR⁸, —SO₂NR⁹R¹⁰, —SO₂R⁸,C(═O)NR⁹R¹⁰; R⁵ is selected from the group consisting of H, andC₁₋₆-alkyl; R⁶, R⁷ are independently selected from the group consistingof H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, aryl,heterocyclyl, heteroaryl, C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁-C₆-alkylsubstituted with aryl, C₁-C₆-alkyl substituted with heteroaryl,C₁-C₆-alkyl substituted with heterocyclyl, or NR⁶R⁷ is NO₂ or R⁶, R⁷together with the N atom to which they are attached can form a saturatedor unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 1ring atom is N and 0, 1, 2, or 3 further ring atoms are selected from N,S, and O, the rest of the ring atoms being C; wherein the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkyloxyor the heterocyclic ring formed by R⁶, R⁷ together with the N atom towhich they are attached is optionally substituted with a substituentselected from the group consisting of C₁₋₆-alkyl, C₃₋₈-cycloalkyl,C₁₋₆-alkyloxy, —NR⁹R¹⁰—, carbonyl, —C(═O)OR⁹—, halogen atom, C₁₋₆-alkylsubstituted with halo, C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl,C₁-C₆-alkyl substituted with aryl, cyano, hydroxyl, —SR⁸—, —SO₂R⁸—,SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰—, C₁₋₆-alkyl substituted with hydroxyl; R⁸ isselected from the group consisting of H, C₁₋₆-alkyl; R⁹, R¹⁰ areindependently selected from the group consisting of H, and C₁₋₆-alkyl; Lis selected from the group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl,—(NR^(L3))₀₋₁—(CH₂)₀₋₄—NR^(L3)—(CH₂)₀₋₄—,—(NR^(L3))₀₋₁—(CR^(L1)R^(L2))₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—,—(CR^(L1)R^(L2))₀₋₄—O—(CR^(L1)R^(L2))—,—(CH₂)₀₋₄—NR^(L3)—(CR^(L1)R^(L2))—C(═O)NH—(CH₂)₀₋₄—,—C(═O)—(CR^(L1)R^(L2))—NR^(L3)C(═O)—, —C(═O)NR^(L3)—, —NR^(L3)C(═O)—,—NR^(L3)—, —SO₂NR^(L3)—, —NR^(L3)—C(═O)—NR^(L3)—; wherein R^(L1),R^(L2), R^(L3), are independently selected from the group consisting ofH, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁-C₆-alkyl substituted with aryl,C₁-C₆-alkyl substituted with heteroaryl, C₁-C₆-alkyl substituted withheterocyclyl; or R^(L1), R^(L3) together with the atoms to which theyare attached can form a saturated or unsaturated heterocyclic ringhaving 3 to 8 ring atoms, wherein 1, 2, or 3, ring atoms are selectedfrom N, S, and O; M is selected from the group consisting ofC₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl, C₂₋₄alkenyl,C₂₋₄alkynyl, —C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1))—, whereineach cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionallysubstituted with a substituent selected from the group consisting ofC₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(M2)R^(M3), carbonyl,—C(═O)OR^(M2), halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl,heteroaryl, C₁-C₆-alkyl substituted with aryl, cyano, hydroxy, —SR^(M2),—SO₂R^(M4), —OSO₂R^(M4), —SO₂NR^(M2)R^(M3), —C(═O)NR^(M2)R^(M3)—,hydroxy-C₁₋₆-alkyl; wherein R^(M1) is selected from the group consistingof H, C₁₋₆-alkyl, halo, hydroxyl, and amino; wherein R^(M2), R^(M3) areindependently selected from the group consisting of H, and C₁₋₆-alkyl;wherein R^(M4) is selected from the group consisting of H, C₁₋₆-alkyl,and amino; G is selected from the group consisting of—(C(R^(G2)R^(G3))₀₋₄—O—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—S—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)(C(R^(G2)R^(G3))₀₋₄—, —C(═O)—,—NR^(G1)C(═O)—, —C(═O)NR^(G1),—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—C(R^(G2)R^(G3))—C(═O)NR^(G1)—,—CR^(G2)═CR^(G2)—, —CR^(G2)═CR^(G2)—CR^(G2)═CR^(G2)—, —C≡C—, —C≡C—C≡C—,—CR^(G2)═CR^(G2)—C≡C, —C≡C—CR^(G2)═CR^(G2), —C(═O)—C≡C—, —C≡C—C(═O)—,—SO₂—, —S(═O)—, —S(═O)C(R^(G2)R^(G3))—, —C(R^(G2)R^(G3))S(═O)—,—C(R^(G2)R^(G3))—SO₂—, —SO₂C(R^(G2)R^(G3))—; wherein R^(G1) is H orC₁₋₆-alkyl each R^(G2), R^(G3) is independently selected from the groupconsisting of H, halogen atom, or C₁₋₆-alkyl; Y is selected from thegroup consisting of C₃₋₁₀-cycloalkyl, aryl, heterocyclyl, heteroaryl,wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionallysubstituted with a substituent selected from the group consisting ofC₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, NR^(Y1)R^(Y2), carbonyl,—C(═O)—OR^(Y1), halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl,heteroaryl, C₁-C₆-alkyl substituted with aryl, cyano, hydroxy, —SR^(Y2),—SO₂R^(Y3), —OSO₂R^(Y3), —SO₂NR^(Y1)R^(Y2), —C(═O)NR^(M2)R^(M3)—,hydroxy-C₁₋₆-alkyl; wherein R^(Y1), R^(Y2) are independently selectedfrom the group consisting of H, and C₁₋₆-alkyl; wherein R^(Y3) isselected from the group consisting of H, C₁₋₆-alkyl, and amino; X isselected from the group consisting of —C(═O)—, —C₁₋₆-alkyl-C(═O)—,—C₂₋₆-alkenyl-C(═O)—, —C₂₋₆-alkynyl-C(═O)—, and —(C(R^(X1)R^(X2))—,—S(═O)—, —SO₂—; wherein each R^(X1), R^(X2) is selected from the groupconsisting of H, halogen atom, substituted C₁₋₆-alkyl, or un-substitutedC₁₋₆-alkyl; wherein the substituents on the substituted C₁₋₆-alkyl maybe selected from the group consisting of halogen, hydroxyl, alkoxy,aryloxy, ester, thiol, C₁₋₆-alkyl, carbonyl, —SR^(X3), —SO₂R^(X5),—C(═O)NR^(X3)R^(X4), cyano, — NR^(X3)R^(X4), —C(═O)—OR^(X3), aryl,heteroaryl, heterocycle, C₃₋₈-cycloalkyl; wherein R^(X3), R^(X4) areindependently selected from the group consisting of H, or C₁₋₆-alkyl;wherein R^(X5) is selected from the group consisting of H, C₁₋₆-alkyl,and amine.
 2. A compound according to claim 1, wherein R⁶, R⁷ areindependently selected from the group consisting of H, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkyloxy-C₁₋₆-alkyl, C₁-C₆-alkylsubstituted with aryl, C₁-C₆-alkyl substituted with heteroaryl, or NR⁶R⁷is NO₂ or R⁶, R⁷ together with the N atom to which they are attached canform a saturated or unsaturated heterocyclic ring having 3 to 12 ringatoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further ringatoms are selected from N, S, and O; wherein the alkyl, alkenyl,cycloalkyl, aryl, heteroaryl, alkyloxy or the heterocyclic ring formedby R⁶, R⁷ together with the N atom to which they are attached isoptionally substituted with a substituent selected from the groupconsisting of C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyloxy, —NR⁹R¹⁰,carbonyl, —C(═O)—OR⁹, halogen atom, C₁₋₆-alkyl substituted with halo,C₁₋₆-alkyloxy-C₁₋₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl substituted witharyl, cyano, hydroxy, —SR⁸, —SO₂R⁸, —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, C₁₋₆-alkylsubstituted with hydroxyl.
 3. A compound according to anyone of claims1-2, wherein L is selected from the group consisting of C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, —NR^(L3)—, wherein R^(L3),is selected from the group consisting of H, C₁₋₆-alkyl, halo-C₁₋₆-alkyl,C₁-C₆-alkyl substituted with aryl, C₁-C₆-alkyl substituted withheteroaryl, C₁-C₆-alkyl substituted with heterocyclyl, preferablywherein L is selected from the group consisting of —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂—.
 4. A compound according to anyone ofclaims 1-3, wherein M is selected from the group consisting of phenyl,thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, pyrazinyl, pyranyl, thiopyranyl, oxazinyl,thiazynyl, —C(R^(M1))═C(R^(M1))—C≡C—, —C(R^(M1))═C(R^(M1)).
 5. Acompound according to anyone of claims 1-4, wherein G is selected fromthe group consisting of —(C(R^(G2)R^(G3))₀₋₄—O—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—S—(C(R^(G2)R^(G3))₀₋₄—,—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—(C(R^(G2)R^(G3))₀₋₄—, —C(═O)—,—NR^(G1)C(═O)—, —C(═O)NR^(G1)—,—(C(R^(G2)R^(G3))₀₋₄—NR^(G1)—C(R^(G2)R^(G3))—C(═O)NR^(G1)—,—CR^(G2)═CR^(G2)—, —C≡C—, —C≡C—C≡C—, —C≡C—C(═O)— —SO₂—, —S(═O)—,—S(═O)C(R^(G2)R^(G3))—, —C(R^(G2)R^(G3))S(═O)—, —C(R^(G2)R^(G3))—SO₂—,—SO₂C(R^(G2)R^(G3))—; wherein R^(G1) is H or C₁₋₆-alkyl each R^(G2),R^(G3) is independently selected from the group consisting of H, halogenatom, or C₁₋₆-alkyl.
 6. A compound according to anyone of claims 1-5,wherein G is selected from the group consisting of —CR^(G2)═CR^(G2)—,—C≡C—, —C≡C—C≡C—, —C≡C—C(═O)—; wherein R^(G2) is selected from the groupconsisting of H, halogen atom, or C₁₋₆-alkyl.
 7. A compound according toanyone of claims 1-6, wherein when R¹³ is OH and R¹² is methyl then R¹¹cannot be methyl.
 8. A compound according to anyone of claims 1-7,wherein when R¹³ is NH₂ and R¹² is H then R¹¹ cannot be H.
 9. A compoundaccording to anyone of claims 1-8, wherein X is selected from the groupconsisting of —C(═O)—, and —S(═O).
 10. A compound according to anyone ofclaims 1-9, wherein R², R³ is independently selected from the groupconsisting of H, substituted C₁₋₆-alkyl, or un-substituted C₁₋₆-alkyl,wherein the substituents on the substituted C₁₋₆-alkyl is selected fromthe group consisting of halogen, hydroxyl, C₁₋₆-alkyl, carbonyl, —SR⁸,—SO₂R⁸, —SO₂NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, cyano, —NR⁹R¹⁰, —C(═O)—OR⁹.
 11. Acompound according to anyone of claims 1-10, wherein R⁴ is selected fromthe group consisting of H, C₁₋₆-alkyl, —OR⁸, C(═O)OR⁸, C(═O)R⁸.
 12. Acompound according to anyone of claims 1-11, wherein Y is selected fromaryl, or heteroaryl.
 13. A pharmaceutical composition comprising acompound according to anyone of claims 1-12 and a pharmaceuticalacceptable carrier.
 14. A compound according to anyone of claims 1-12for use in the treatment of bovine respiratory disease or swinerespiratory disease.
 15. A compound according to anyone of claims 1-12for, for use in the treatment of an infection caused by a bacteria in ananimal wherein the bacteria is at least one of the bacteria selectedfrom the group Pasteurella multocida, Mannheimia haemolytica andHistophilus somni comprising administering an effective amount of acompound according to anyone of claims 1-12 to an animal in needthereof.